DAta | National Center for Advancing Translational Sciences

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18585	Commonly Used Antibiotic Shows Promise for Combating Zika Infections	In a preclinical study, NIH scientists found that the commonly used antibiotic methacycline may be effective at combating the neurological problems caused by Zika virus infections. Here is a picture of a Zika-infected mouse brain from the study. (Courtesy of Nath lab NIH/NINDS)November 24, 2020NIH preclinical study suggests FDA-approved tetracycline-based antibiotics may slow infection and reduce neurological problemsIn 2015, hundreds of children were born with brain deformities resulting from a global outbreak of Zika virus infections. Recently, National Institutes of Health researchers used a variety of advanced drug screening techniques to test out more than 10,000 compounds in search of a cure. To their surprise, they found that the widely used antibiotic methacycline was effective at preventing brain infections and reducing neurological problems associated with the virus in mice. In addition, they found that drugs originally designed to combat Alzheimer’s disease and inflammation may also help fight infections.“Around the world, the Zika outbreak produced devastating, long-term neurological problems for many children and their families. Although the infections are down, the threat remains,” said Avindra Nath, M.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and a senior author of the study published in PNAS. “We hope these promising results are a good first step to preparing the world for combating the next potential outbreak.”The study was a collaboration between scientists on Nath’s team and researchers in laboratories led by Anton Simeonov, Ph.D., scientific director at NCATS and Radhakrishnan Padmanabhan, Ph.D., Professor of Microbiology & Immunology, Georgetown University Medical Center, Washington, D.C.The Zika virus is primarily spread by the Aedes aegypti mosquito. In 2015 and 2016, at least 60 countries reported infections. Some of these countries also reported a high incidence of infected mothers giving birth to babies born with abnormally small heads resulting from a developmental brain disorder called fetal microcephaly. In some adults, infections were the cause of several neurological disorders including Guillain-Barré syndrome, encephalitis, and myelitis. Although many scientists have tried, they have yet to discover an effective treatment or vaccination against the virus.In this study, the researchers looked for drugs that prevent the virus from reproducing by blocking the activity of a protein called NS2B-NS3 Zika virus protease. The Zika virus is a protein capsule that carries long strings of RNA-encoded instructions for manufacturing more viral proteins. During an infection, the virus injects the RNA into a cell, resulting in the production of these proteins, which are strung together, side-by-side, like the parts in a plastic model airplane kit. The NS2B-NS3 protease then snaps off each protein, all of which are critical for assembling new viral particles.“Proteases act like scissors. Blocking protease activity is an effective strategy for counteracting many viruses,” said Rachel Abrams, Ph.D., an organic chemist in Nath’s lab and the study leader. “We wanted to look as far and wide as possible for drugs that could prevent the protease from snipping the Zika virus polyprotein into its active pieces.”To find candidates, Abrams worked with scientists on Simeonov’s and Padmanabhan’s teams to create assays, or tests, for assessing the ability of drugs to block NS2B-NS3 Zika virus protease activity in plates containing hundreds of tiny test tubes. Each assay was tailored to a different screening, or sifting, technique. They then used these assays to simultaneously try out thousands of candidates stored in three separate libraries.One preliminary screen of 2,000 compounds suggested that commonly used, tetracycline-based antibiotic drugs, like methacycline, may be effective at blocking the protease.Meanwhile, a large-scale screen of more than 10,000 compounds helped identify an investigational anti-inflammatory medicine, called MK-591, and a failed anti-Alzheimer’s disease drug, called JNJ-404 as potential candidates. A virtual screen of over 130,000 compounds was also used to help spot candidates. For this, the researchers fed the other screening results into a computer and then used artificial intelligence-based programs to learn what makes a compound good at blocking NS2B-NS3 Zika virus protease activity.“These results show that taking advantage of the latest technological advances can help researchers find treatments that can be repurposed to fight other diseases,” said Simeonov.The Zika virus is known to preferentially infect stem cells in the brain. Scientists suspect this is the reason why infections cause more harm to newborn babies than to adults. Experiments on neural stem cells grown in petri dishes indicated that all three drugs identified in this study may counteract these problems. Treating the cells with methacycline, MK-591, or JNJ-404 reduced Zika virus infections.Because tetracyclines are U.S. Food and Drug Administration-approved drugs that are known to cross the placenta of pregnant women, the researchers focused on methacycline and found that it may reduce some neurodevelopmental problems caused by the Zika virus. For instance, Zika-infected newborn mice that were treated with methacycline had better balance and could turn over more easily than ones that were given a placebo. Brain examinations suggested this was because the antibiotic reduced infections and neural damage. Nevertheless, the antibiotics did not completely counteract harm caused by the Zika virus. The weight of mice infected with the virus was lower than control mice regardless of whether the mice were treated with methacycline.“These results suggest that tetracycline-based antibiotics may at least be effective at preventing the neurological problems associated with Zika virus infections,” said Abrams. “Given that they are widely used, we hope that we can rapidly test their potential in clinical trials.”Article:Abrams, R.P.M., Yasgar, A. et al., Therapeutic Candidates for the Zika Virus Identified by a High Throughput Screen for Zika Protease Inhibitors. PNAS, November 23, 2020 DOI: 10.1073/pnas.2005463117.These studies were supported by NIH Intramural Research Programs at NINDS and NCATS (TR000291) and an NIH grant (AI109185).NCATS Media Contact: NCATS Information Officer, ncatsinfo@mail.nih.govNINDS Media Contact: Christopher G. Thomas, nindspressteam@ninds.nih.govAbout the National Institute of Neurological Disorders and Stroke (https://www.ninds.nih.gov) is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.About the National Center for Advancing Translational Sciences (NCATS): NCATS conducts and supports research on the science and operation of translation — the process by which interventions to improve health are developed and implemented — to allow more treatments to get to more patients more quickly. For more information about how NCATS helps shorten the journey from scientific observation to clinical intervention, visit https://ncats.nih.gov.About the National Institute of Allergy and Infectious Diseases: NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit https://www.nih.gov.NIH…Turning Discovery Into Health®	NIH study suggests FDA-approved antibiotics may slow Zika infection and reduce neurological problems	/sites/default/files/Zika_release_900x600_0.jpg	Commonly Used Antibiotic Shows Promise for Combating Zika Infections	NIH study suggests FDA-approved antibiotics may slow Zika infection and reduce neurological problems	/sites/default/files/Zika_release_900x600_1.jpg	Commonly Used Antibiotic Shows Promise for Combating Zika Infections
18531	Informatics	Informatics OverviewInformatics plays a key role in organizing, processing, analyzing, and interpreting the large quantity and variety of data generated in translational research. The Informatics (IFX) Core covers a wide array of expertise, including bioinformatics, multi-omics, cheminformatics, clinical informatics, data science, software engineering, UI/UX research and design, and project management. IFX Core team members collaborate extensively with informaticians embedded in other branches and cores of DPI and with other colleagues across DPI to produce methodologies, resources and software for the translational research community.IFX Core MissionThe mission of the NCATS IFX Core is to derive actionable insights from integrating translational research data and to accelerate translation of findings into the clinic by:• Identifying biological and chemical mechanisms that underlie diseases, including rare diseases, and their development, drug mechanisms of action and treatment response using novel or existing methods• Improving use and interpretation of metabolomics and other omics datasets by developing new methods or enhancing the application of existing methods• Producing open, comprehensive resources to accelerate translational research efforts, spanning ingredient/drug regulatory information, target annotations, disease annotations and molecular/omic phenotypes• Producing tools for the analysis and interpretation of complex high-throughput datasets• Developing, optimizing and testing models to prioritize targets and therapeutic opportunities, and identifying repurposed drugs through collaborations with NCATS’ DPI branches• Enhancing transparency and open research by adhering to user-centric and FAIR (Findable, Accessible, Interoperable, Reproducible) best practices• Assessing productivity of the translational research process• Expanding the use and understanding of informatics in translational research through workshops, training and mentoringWhat We DoEfforts within the IFX Core can be categorized into three main parts:• Building Standards, Knowledge Sources and Software: Integration, curation and public rendering to support analysis of various types of experimental and curated datasets• Translational Data Analytics: Development of custom workflows and new methodologies to help interpret complex, large-scale datasets, including multi-omic and clinical data• Scientific Computing Services and Research: Development, maintenance and deployment of cheminformatics and bioinformatics workflows/pipelines; web and mobile apps to disseminate our robust methods and data; bioinformatics and cheminformatics collaborative work with non-informaticians (within and beyond NCATS)These three components are coordinated through our governance structure and efforts where one component informs efforts in another.Contact Ewy Mathé, Ph.D.	Informatics scientists at NCATS collaborate closely with other investigators and develop algorithms and software to disseminate results.		Informatics	Informatics scientists at NCATS collaborate closely with other investigators and develop algorithms and software to disseminate results.		Informatics
18291	Cures Acceleration Network Review Board Real-World Applications for Mature Programs (RAMP) Working Group	Charge In 2019, NCATS established a Cures Acceleration Network Review Board (CAN RB) working group to assess how NCATS can accelerate translational science implementation and foster the uptake of mature CAN RB-supported tools and technologies into real-world use and practice. The CAN RB Real-World Applications for Mature Programs (RAMP) working group is charged with making recommendations that will enable NCATS to better leverage the power and authorities of the CAN RB to transition translational science projects towards real-world utilization in vehicles that are independent of NCATS support. The CAN RB RAMP working group will provide input on how NCATS might best transition the current 4 CAN RB mature programs towards real-world applications and make recommendations on general principles that inform the design, selection and prioritization of new projects such that facilitating transition to real-world applications is built into future project proposals. The CAN RB RAMP working group is currently in progress and is expected to deliver formal recommendations to the CAN RB in spring 2021. Related Reports “Maximizing the Goals of the Cures Acceleration Network to Accelerate the Development of New Drugs and Diagnostics: A Workshop” took place June 4–5, 2012. Review the workshop summary (PDF - 601KB) or visit the National Academy of Medicine (formerly the Institute of Medicine) website for more information about this event. Roster CO-CHAIRS Chairperson Ronald J. Bartek, M.A. Co-Founder and Founding President Friedreich’s Ataxia Research Alliance Arlington, Virginia Vice Chairperson Gilbert “Lynn” Marks, M.D. Senior Advisor Tunnell Government Services Cape May, New Jersey MEMBERS Margaret Anderson Managing Director Deloitte Consulting, LLP Rosslyn, Virginia Christopher Flores, Ph.D. Vice President, Neuroscience Therapeutic Area Janssen Research & Development San Diego, California Christopher Gibson, Ph.D. Co-Founder and CEO Recursion Pharmaceuticals Salt Lake City, Utah Kathy Hudson, Ph.D. Founder and Consultant Hudson Works, LLC Washington, D.C. Geoffrey Ling, M.D., Ph.D. Professor of Neurology Johns Hopkins University Baltimore, Maryland Peter Marks, M.D., Ph.D. Director Center for Biologics Evaluation and Research (CBER) U.S. Food and Drug Administration Silver Spring, Maryland Megan O’Boyle Principal Investigator Phelan-McDermid Syndrome Data Network Arlington, Virginia Alan Palkowitz, Ph.D. Senior Research Professor of Medicine University School of Medicine Indianapolis, Indiana Mary Perry, Ph.D. Program Leader Office of Strategic Coordination Division of Program Coordination, Planning, and Strategic Initiatives Office of the Director National Institutes of Health Bethesda, Maryland Elizabeth Stoner, M.D. Executive Partner MPM Capital New York, New York Laura Lyman Rodriguez, Ph.D. Interim Chief Program Support Officer, Senior Advisor to the Executive Director Patient-Centered Outcomes Research Institute Washington, D.C. David Wholley, M.Phil. Senior Vice President, Research Partnerships Foundation for the National Institutes of Health Bethesda, Maryland EX OFFICIO Anna Ramsey-Ewing, Ph.D. Director Division of Extramural Activities National Center for Advancing Translational Sciences National Institutes of Health Bethesda, Maryland EXECUTIVE SECRETARY Samantha G. Jonson, M.P.S. Dissemination and Implementation Strategy Lead Office of the Director National Center for Advancing Translational Sciences National Institutes of Health Bethesda, Maryland			Cures Acceleration Network Review Board (CAN RB)			Cures Acceleration Network Review Board (CAN RB)
18228	About Informatics Research and Scientific Applications in the Division of Preclinical Innovation Informatics Core	li { color: #000; } .panel { margin: 0 14px 20px; } .panel-heading, p > strong, li > strong { color: #333; } .panel-body { padding: 15px 15px 5px; } Informatics plays a key role in organizing, processing, analyzing, and interpreting the large quantity and variety of data generated in translational research. The Informatics (IFX) Core, led by Ewy Mathé, Ph.D., within the Division of Preclinical Innovation (DPI) covers a wide array of expertise, including bioinformatics, cheminformatics, clinical informatics, data science, software engineering, UI/UX research and design, and project management. IFX Core team members collaborate extensively with informaticians embedded in other branches and cores of DPI and with other colleagues across DPI to produce methodologies, resources and software for the translational research community. On this page: IFX Core Mission Who We Are What We Do Whom We Work With Select Publications IFX Core Mission The mission of the NCATS IFX Core is to produce data-driven decisions and accelerate translation by: Identifying biological and chemical mechanisms that underlie diseases, including rare diseases, and their development, drug mechanisms of action, and treatment response using novel or existing methods Improving use and interpretation of metabolomics and other omics datasets by developing new methods or enhancing the application of existing methods Producing open, comprehensive resources to accelerate translational research efforts, spanning ingredient/drug regulatory information, target annotations, disease annotations and molecular/omic phenotypes Producing tools for the analysis and interpretation of complex high-throughput datasets Developing, optimizing and testing models to prioritize targets and therapeutic opportunities, and identifying repurposed drugs through collaborations with NCATS’ DPI branches Enhancing transparency and open research by adhering to user-centric and FAIR (Findable, Accessible, Interoperable, Reproducible) best practices Assessing productivity of the translational research process Expanding the use and understanding of informatics in translational research through workshops, training and mentoring Who We Are Our work is highly collaborative, and we take a team science approach in which everyone contributes meaningfully to translational research projects. We also are excited to house a number of trainees, from Ph.D. students to postdoctoral fellows, who bring in fresh ideas to our work. Learn more about the informatics scientists in DPI. What We Do Efforts within the IFX Core can be categorized into 3 main parts: Building Standards, Knowledge Sources and Software: Integration, curation and public rendering to support analysis of various types of experimental and curated datasets. Translational Data Analytics: Development of custom workflows and new methodologies to help interpret complex, large-scale datasets, including multi-omic and clinical data. Scientific Computing Services and Research: Development, maintenance and deployment of cheminformatics and bioinformatics workflows/pipelines, web and mobile apps to disseminate our robust methods and data; bioinformatics and cheminformatics collaborative work with non-informaticians (within and beyond NCATS). These three components are coordinated through our governance structure and efforts where one component informs efforts in another. See below for our publications. Learn more about each component — Building Standards, Knowledge Sources and Software Translational Data Analytics Scientific Computing Services and Research Whom We Work With Within NCATS Division of Preclinical Innovation Division of Clinical Innovation Division of Rare Diseases Research Innovation Other Institutes and Centers at NIH National Cancer Institute National Center for Biotechnology Information National Institute of Diabetes and Digestive and Kidney Diseases National Heart, Lung, and Blood Institute National Human Genome Research Institute NIH Common Fund — Illuminating the Druggable Genome Other Partners and Collaborators Brigham and Women’s Hospital and Harvard Medical School U.S. Food and Drug Administration Cures Acceleration Network Critical Path Institute The Ohio State University The University of New Mexico Select Publications Featured Publications Sheils T, Mathias S, Kelleher K, et al. TCRD and Pharos 2020: Mining the human proteome for disease biology. Nucleic Acids Res. 2020 (49). PMID:33156327 Siramshetty V, Williams J, Nguyễn ÐT, et al. Validating ADME QSAR Models Using Marketed Drug. SLAS Discov, 2021. PMID:34176369 Peryea T, Southall N, Miller M, et al. Global Substance Registration System: consistent scientific descriptions for substances related to health. Nucleic Acids Res, 2021 (49). PMID:33137173 2021 See More Gonzalez E, Jain S, Shah P, et al. Development of robust QSAR models for CYP2C9, CYP2D6, and CYP3A4 catalysis and inhibition. Drug Metab and Dispos. 21 Sep;49(9):822-832. doi: 10.1124/dmd.120.000320. PMID:34183376. Pace BS, Perrine S, Li B, et al. Benserazide racemate and enantiomers induce fetal globin gene expression in vivo: studies to guide clinical development for beta thalassemia and sickle cell disease. Blood Cells Mols Dis. 2021 Jul;89:102561. doi: 10.1016/j.bcmd.2021.102561. PMID: 33744514. Christov PP, Kim K, Jana S, et al. Optimization of ether and aniline based inhibitors of lactate dehydrogenase. Bioorg Med Chem Lett. 2021 Jun 1;41:127974. doi: 10.1016/j.bmcl.2021.127974. PMID: 33771585. Gorshkov K, Chen CZ, Bostwick R, et al. The SARS-CoV-2 cytopathic effect is blocked by lysosome alkalizing small molecules. ACS Infect Dis. 2021 Jun 11;7(6):1389-1408. doi: 10.1021/acsinfecdis.0c00349. PMID: 33346633. Martinez NJ, Braisted JC, Dranchak PK, et al. Genome-edited coincidence and PMP22-HiBiT fusion reporter cell lines enable an artifact-suppressive quantitative high-throughput screening strategy for PMP22 gene-dosage disorder drug discovery. ACS Pharmacol Transl Sci. 2021 Jun 10;4(4):1422-1436. doi: 10.1021/acsptsci.1c00110. PMID: 34423274. Murai Y, Jo U, Murai J, et al. SLFN11 inactivation induces proteotoxic stress and sensitizes cancer cells to ubiquitin activating enzyme inhibitor TAK-243. Cancer Res. 2021 Jun 1;81(11):3067-3078. doi: 10.1158/0008-5472.CAN-20-2694. PMID: 33863777. Ryu S, Chu PH, Malley C, et al. Human pluripotent stem cells for high-throughput drug screening and characterization of small molecules. Methods Mol Biol. 2021 Jun 15. Epub ahead of print. PMID: 34128205. Siramshetty V, Williams J, Nguyễn ÐT, et al. Validating ADME QSAR models using marketed drugs. SLAS Discov. 2021 Jun 26:24725552211017520. doi: 10.1177/24725552211017520. PMID: 34176369. Son J, Huang S, Zeng Q, et al. JIB-04 has broad-spectrum antiviral activity and inhibits SARS-CoV-2 replication and coronavirus pathogenesis. bioRxiv [Preprint]. 2021 Jun 4:2020.09.24.312165. doi: 10.1101/2020.09.24.312165. PMID: 32995798. Tan MSY, Koussis K, Withers-Martinez C, et al. Autocatalytic activation of a malarial egress protease is druggable and requires a protein cofactor. EMBO J. 2021 Jun 1;40(11):e107226. doi: 10.15252/embj.2020107226. PMID: 33932049. Wiedmann M, Dranchak PK, Aitha M, et al. Structure-activity relationship of ipglycermide binding to phosphoglycerate mutases. J Biol Chem. 2021 Jan-Jun;296:100628. doi: 10.1016/j.jbc.2021.100628. PMID: 33812994. Chen Y, Tristan CA, Chen L, et al. A versatile polypharmacology platform promotes cytoprotection and viability of human pluripotent and differentiated cells. Nat Methods. 2021 May;18(5):528-541. doi: 10.1038/s41592-021-01126-2. PMID: 33941937. John JN, Sid E, Zhu Q. Recurrent neural networks to automatically identify rare disease epidemiologic studies from PubMed. AMIA Annu Symp Proc. 2021 May 17;2021:325-334. PMID: 34457147. Shamim K, Xu M, Hu X, et al. Application of niclosamide and analogs as small molecule inhibitors of Zika virus and SARS-CoV-2 infection. Bioorg Med Chem Lett. 2021 May 15;40:127906. doi: 10.1016/j.bmcl.2021.127906. PMID: 33689873. Henderson MJ, Trychta KA, Yang SM, et al. A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome. Cell Rep. 2021 Apr 27;35(4):109040. doi: 10.1016/j.celrep.2021.109040. PMID: 33910017. Li J, Wu R, Yung MMH, et al. SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance. Cell Death Dis. 2021 Apr 1;12(4):341. doi: 10.1038/s41419-021-03635-6. PMID: 33795649. Li S, Zhao J, Huang R, et al. Profiling the Tox21 chemical collection for acetylcholinesterase inhibition. Environ Health Perspect. 2021 Apr;129 (4):47008. doi: 10.1289/EHP6993. PMID: 33844597. Mansouri K, Karmaus AL, Fitzpatrick J, et al. CATMoS: collaborative acute toxicity modeling suite. Environ Health Perspect. 2021 Apr;129(4):47013. doi: 10.1289/EHP8495. PMID: 33929906. Rohde JM, Karavadhi S, Pragani R, et al. Discovery and optimization of 2H-1λ2-Pyridin-2-one inhibitors of mutant isocitrate dehydrogenase 1 for the treatment of cancer. J Med Chem. 2021 Apr 22;64(8):4913-4946. doi: 10.1021/acs.jmedchem.1c00019. PMID: 33822623. Temprosa M, Moore SC, Zanetti KA, et al. COMETS Analytics: an online tool for analyzing and meta-analyzing metabolomics data in large research consortia. Am J Epidemiol. 2021 Apr 22:kwab120. doi: 10.1093/aje/kwab120. PMID: 33889934. Thomas A, Takahashi N, Rajapakse VN, et al. Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress. Cancer Cell. 2021 Apr 12;39 (4):566-579.e7. doi: 10.1016/j.ccell.2021.02.014. PMID: 33848478. Cheng YS, Roma JS, Shen M, et al. Identification of antifungal compounds against multidrug-resistant Candida auris utilizing a high-throughput drug-repurposing screen. Antimicrob Agents and Chemother. 2021 Mar 18;65(4):e01305-20. doi: 10.1128/AAC.01305-20. PMID: 33468482. Fecho K, Balhoff J, Bizon C, et al. Application of MCAT questions as a testing tool and evaluation metric for knowledge graph-based reasoning systems. Clin Transl Sci. 2021 Mar 20. doi: 10.1111/cts.13021. PMID: 33742785. Hu X, Shrimp JH, Guo H, et al. Discovery of TMPRSS2 inhibitors from virtual screening. bioRxiv [Preprint]. 2021 Mar 17:2020.12.28.424413. doi: 10.1101/2020.12.28.424413. PMID: 33398276. Khaled HG, Feng H, Hu X, et al. A high-throughput screening to identify small molecules that suppress huntingtin promoter activity or activate huntingtin-antisense promoter activity. Sci Rep. 2021 Mar 17;11(1):6157. doi: 10.1038/s41598-021-85279-2. PMID: 33731741. Li S, Zhang L, Huang R, et al. Evaluation of chemical compounds that inhibit neurite outgrowth using GFP-labeled iPSC-derived human neurons. Neurotoxicology. 2021 Mar;83:137-145. doi: 10.1016/j.neuro.2021.01.003. PMID: 33508353. Liao G, Ye W, Heitmann T, et al. Identification of small-molecule inhibitors of human inositol hexakisphosphate kinases by high-throughput screening. ACS Pharmacol Transl Sci. 2021 Mar 3;4(2):780-789. doi: 10.1021/acsptsci.0c00218. PMID: 33860201. Bobrowski T, Chen L, Eastman RT, et al. Synergistic and antagonistic drug combinations against SARS-CoV-2. Mol Ther. 2021 Feb 3;29(2):873-885. doi: 10.1016/j.ymthe.2020.12.016. PMID: 33333292. Jain S, Siramshetty VB, Alves VM, et al. Large-scale modeling of multispecies acute toxicity end points using consensus of multitask deep learning methods. J Chem Inf Model. 2021 Feb 22;61(2):653-663. doi: 10.1021/acs.jcim.0c01164. PMID: 33533614. Jo U, Murai Y, Chakka S, et al. SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors. Proc Natl Acad Sci U S A. 2021 Feb 9;118(6):e2015654118. doi: 10.1073/pnas.2015654118. PMID: 33536335. Le Manach C, Dam J, Woodland JG, et al. Identification and profiling of a novel diazaspiro[3.4]octane chemical series active against multiple stages of the human malaria parasite Plasmodium falciparum and optimization efforts. J Med Chem. 2021 Feb 25;64(4):2291-2309. doi: 10.1021/acs.jmedchem.1c00034. PMID: 33573376. Lynch C, Sakamuru S, Huang R, Niebler J, Ferguson SS, Xia M. Characterization of human pregnane X receptor activators identified from a screening of the Tox21 compound library. Biochem Pharmacol. 2021 Feb;184:114368. doi: 10.1016/j.bcp.2020.114368. PMID: 33333074. Song G, Lee EM, Pan J, et al. An integrated systems biology approach identifies the proteasome as a critical host machinery for ZIKV and DENV replication. Genomics Proteomics Bioinformatics. 2021 Feb 19:S1672-0229(21)00025-5. doi: 10.1016/j.gpb.2020.06.016. PMID: 33610792. Wu L, Huang R, Tetko IV, Xia Z, Xu J, Tong W. Trade-off predictivity and explainability for machine-learning powered predictive toxicology: an in-depth investigation with Tox21 data sets. Chem Res Toxicol. 2021 Feb 15;34(2):541-549. doi: 10.1021/acs.chemrestox.0c00373. PMID: 33513003. Avram S, Bologa CG, Holmes J, et al. DrugCentral 2021 supports drug discovery and repositioning. Nucleic Acids Res. 2021 Jan 8;49(D1):D1160-D1169. doi: 10.1093/nar/gkaa997. PMID: 33151287. Chen CZ, Shinn P, Itkin Z, et al. Drug repurposing screen for compounds inhibiting the cytopathic effect of SARS-CoV-2. Front Pharmacol. 2021 Jan 25;11:592737. doi: 10.3389/fphar.2020.592737. PMID: 33708112. Dorjsuren D, Eastman RT, Wicht KJ, et al. Chemoprotective antimalarials identified through quantitative high-throughput screening of Plasmodium blood and liver stage parasites. Sci Rep. 2021 Jan 22;11(1):2121. doi: 10.1038/s41598-021-81486-z. PMID: 33483532. Eicher T, Chan J, Luu H, Machiraju R, Mathé EA. Self-organizing maps with variable neighborhoods facilitate learning of chromatin accessibility signal shapes associated with regulatory elements. BMC Bioinformatics. 2021 Jan 30;22(1):35. doi: 10.1186/s12859-021-03976-1. PMID: 33516170. Peryea T, Southall N, Miller M, et al. Global Substance Registration System: consistent scientific descriptions for substances related to health. Nucleic Acids Res. 2021 Jan 8;49 (D1):D1179-D1185. doi: 10.1093/nar/gkaa962. PMID: 33137173. Sheils TK, Mathias SL, Kelleher KJ, et al. TCRD and Pharos 2021: mining the human proteome for disease biology. Nucleic Acids Res. 2021 Jan 8;49(D1):D1334-D1346. doi: 10.1093/nar/gkaa993. PMID: 33156327. 2020 See More Tong ZB, Braisted J, Chu PH, Gerhold D. The MT1G gene in LUHMES neurons is a sensitive biomarker of neurotoxicity. Neurotox Res. 2020;38(4):967-978. doi:10.1007/s12640-020-00272-3. PMID:32870474. Zhu Q, Nguyen D, Grishagin I, et al. An integrative knowledge graph for rare diseases, derived from the Genetic and Rare Diseases Information Center (GARD). J Biomed Semantics. 2020;11(1):13. doi: 10.1186/s13326-020-00232-y. PMID:. PMCID:PMC7663894 Sheils T, Mathias S, Kelleher K, et al. TCRD and Pharos 2020: Mining the human proteome for disease biology. Nucleic Acids Res. 2020;gkaa993. doi:10.1093/nar/gkaa993. PMID:33156327 Zhu Q, Nguyen DT, Sid E, Pariser A. Leveraging the UMLS as a data standard for rare disease data normalization and harmonization. Methods Inf Med. 2020. doi:10.1055/s-0040-1718940 Peryea, T, Southall, N, Miller, M, et al. Global Substance Registration System: consistent scientific descriptions for substances related to health. Nucleic Acids Res. 2020;gkaa962. doi:10.1093/nar/gkaa962. PMID:33137173. Zhu Q, Nguyen DT, Alyea G, Hanson K, Sid E, Pariser A. Phenotypically similar rare disease identification from an integrative knowledge graph for data harmonization: Preliminary study. JMIR Med Inform. 2020;8(10):e18395. doi:10.2196/18395. PMID:33006565. Patt A, Demoret B, Stets C, et al. MDM2-dependent rewiring of metabolomic and lipidomic profiles in dedifferentiated liposarcoma models. Cancers (Basel). 2020;12(8):2157. doi:10.3390/cancers12082157. PMID:32759684. PMCID:PMC7463633. Tristan CA, Ormanoglu P, Slamecka J, et al. Robotic high-throughput biomanufacturing and functional differentiation of human pluripotent stem cells. bioRxiv. Preprint posted online 2020;2020.08.03.235242. doi:10.1101/2020.08.03.235242. PMID:32793899. PMCID:PMC7418713. Zhao Y, Man-Un Ung P, Zahoránszky-Kőhalmi G, et al. Identification of a G-protein-independent activator of GIRK channels. Cell Rep. 2020;31(11):107770. doi:10.1016/j.celrep.2020.107770. Brimacombe KR, Zhao T, Eastman RT, et al. An OpenData portal to share COVID-19 drug repurposing data in real time. bioRxiv. Preprint posted online 2020;2020.06.04.135046. doi:10.1101/2020.06.04.135046. PMID:32511420. PMCID:PMC7276055. Eicher T, Kinnebrew G, Patt A, et al. Metabolomics and multi-omics integration: A survey of computational methods and resources. Metabolites. 2020;10(5):202. doi:10.3390/metabo10050202. PMID:32429287. PMCID:PMC7281435. Siramshetty VB, Nguyen DT, Martinez NJ, Simeonov A, Southall NT, Zakharov A. Critical assessment of artificial intelligence methods for prediction of hERG channel inhibition in the “big data” era. ChemRxiv. Epub April 16, 2020. doi:10.26434/chemrxiv.12119040.v1. Shah P, Siramshetty VB, Zakharov AV, Southall NT, Xu X, Nguyen DT. Predicting liver cytosol stability of small molecules. J Cheminform. 2020;12:21. Published online 2020 April 7. doi:10.1186/s13321-020-00426-7. PMCID:PMC7140498. Chu PH, Chen G, Kuo D, et al. Stem cell-derived endothelial cell model that responds to tobacco smoke like primary endothelial cells. Chem Res Toxicol. 2020;33(3):751-763. doi:10.1021/acs.chemrestox.9b00363. PMID:32119531. Ellis CR, Racz R, Kruhlak NL, et al. Evaluating kratom alkaloids using PHASE. PLoS One. 2020;15(3):e0229646. doi:10.1371/journal.pone.0229646. eCollection 2020. PMID:32126112. Sheils T, Mathias SL, Siramshetty VB, et al. How to illuminate the druggable genome using Pharos. Curr Protoc Bioinformatics. 2020;69(1):e92. doi:10.1002/cpbi.92. PMID:31898878. Zahoranszky-Kohalmi G, Wan KK, Godfrey AG. (2020): Hilbert-curve assisted structure embedding method. ChemRxiv. Preprint posted online Feb 28, 2020. doi:10.26434/chemrxiv.11911296.v1. Godfrey AG, Michael SG, Sittampalam GS, Zahoránszky-Köhalmi G. A perspective on innovating the chemistry lab bench. Front Robot AI. 2020;7:24. doi:10.3389/frobt.2020.00024. Zahoránszky-Kőhalmi G, Sheils T, Oprea TI. SmartGraph: A network pharmacology investigation platform. J Cheminform. 2020;12:5. doi:10.1186/s13321-020-0409-9. Ansbro MR, Itkin Z, Chen L, et al. Modulation of triple artemisinin-based combination therapy pharmacodynamics by Plasmodium falciparum genotype. ACS Pharmacol Transl Sci. 2020 Nov 2;3(6):1144-1157. doi:10.1021/acsptsci.0c00110. PMID: 33344893. Shah P, Siramshetty VB, Zakharov AV, Southall NT, Xu X, Nguyen DT. Predicting liver cytosol stability of small molecules. J Cheminform. 2020 Apr 7;12(1):21. doi: 10.1186/s13321-020-00426-7. PMID:33431020. Zahoránszky-Kőhalmi G, Sheils T, Oprea TI. SmartGraph: a network pharmacology investigation platform. J Cheminform. 2020 Jan 21;12(1):5. doi: 10.1186/s13321-020-0409-9. PMID:33430980. 2019 See More Peryea T, Katzel D, Zhao T, Southall N, Nguyen DT. MOLVEC: Open source library for chemical structure recognition. In Abstracts of Papers of the American Chemical Society. Vol. 258. Washington, D.C.: American Chemical Society; 2019. Fecho K, Ahalt SC, Arunachalam S, et al.; Biomedical Data Translator Consortium. Sex, obesity, diabetes, and exposure to particulate matter among patients with severe asthma: Scientific insights from a comparative analysis of open clinical data sources during a five-day hackathon. J Biomed Inform. 2019;100:103325. doi:10.1016/j.jbi.2019.103325. PMID:31676459. PMCID:PMC6953386. Huang R, Zhu H, Shinn P, et al. The NCATS Pharmaceutical Collection: A 10-year update. Drug Discov Today. 2019;24(12):2341-2349. doi:10.1016/j.drudis.2019.09.019. PMID:31585169. Zakharov AV, Zhao T, Nguyen DT, et al. Novel consensus architecture to improve performance of large-scale multitask deep learning QSAR models. J Chem Inf Model. 2019;59(11):4613-4624. doi:10.1021/acs.jcim.9b00526. PMID:31584270. Chen Y, Tristan CA, Chen L, et al. A versatile polypharmacology platform promotes cytoprotection and viability of human pluripotent and differentiated cells. bioRxiv. Preprint posted online Oct 22, 2019. doi:10.1101/815761. Southall NT, Natarajan M, Lau LPL, et al.; IRDiRC Data Mining and Repurposing Task Force. The use or generation of biomedical data and existing medicines to discover and establish new treatments for patients with rare diseases — recommendations of the IRDiRC Data Mining and Repurposing Task Force. Orphanet J Rare Dis. 2019;14(1):225. doi:10.1186/s13023-019-1193-3. PMID:31615551. Southall NT. Freedom of Information Act access to an investigational new drug application. ACS Pharmacol Transl Sci. 2019;2(6):497-500. doi:10.1021/acsptsci.9b00056. eCollection 2019 Dec 13. PMID:32259081. Solinski HJ, Dranchak P, Oliphant E, et al. Inhibition of natriuretic peptide receptor 1 reduces itch in mice. Sci Transl Med. 2019;11(500):eaav5464. doi:10.1126/scitranslmed.aav5464. PMID:31292265. PMCID:PMC7218920. Huang R, Grishagin I, Wang Y, et al. The NCATS BioPlanet — An integrated platform for exploring the universe of cellular signaling pathways for toxicology, systems biology, and chemical genomics. Front Pharmacol. 2019;10:445. doi:10.3389/fphar.2019.00445. eCollection 2019. PMID:31133849. Austin CP, Colvis CM, Southall NT. Deconstructing the translational Tower of Babel. Clin Transl Sci. 2019;12(2):85. doi:10.1111/cts.12595. Epub 2018 Nov 9. PMID:30412342. Gorshkov K, Chen CZ, Marshall RE, et al. Advancing precision medicine with personalized drug screening. Drug Discov Today. 2019;24(1):272-278. doi:10.1016/j.drudis.2018.08.010. PMID:30125678. 2018 See More Kearney SE, Zahoránszky-Kőhalmi G, Brimacombe KR, et al. Canvass: A crowd-sourced, natural-product screening library for exploring biological space. ACS Central Science. 2018;4(12):1727-1741. doi:10.1021/acscentsci.8b00747. PMID:30648156. Zhou W, Sun W, Yung MMH, et al. Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance. Oncogene. 2018;37(29):3981-3997. doi:10.1038/s41388-018-0238-8. PMID:29662190. PMCID:PMC6054535. Oprea TI, Bologa CG, Brunak S, et al. Unexplored therapeutic opportunities in the human genome. Nat Rev Drug Discov. 2018;17(5):317-332. doi:10.1038/nrd.2018.14. PMID:29472638. Tong ZB, Huang R, Wang Y, et al. The Toxmatrix: Chemo-genomic profiling identifies interactions that reveal mechanisms of toxicity. Chem Res Toxicol. 2018;31(2):127-136. doi:10.1021/acs.chemrestox.7b00290. PMID:29156121. Coussens NP, Braisted JC, Peryea T, Sittampalam GS, Simeonov A, Hall MD. Small-molecule screens: A gateway to cancer therapeutic agents with case studies of Food and Drug Administration–approved drugs. Pharmacol Rev. 2017;69(4):479-496. doi:10.1124/pr.117.013755. PMID:28931623. PMCID:PMC5612261. Nguyen DT, Mathias S, Bologa C, et al. Pharos: Collating protein information to shed light on the druggable genome. Nucleic Acids Res. 2017;45(D1):D995-D1002. doi:10.1093/nar/gkw1072. PMID:27903890. PMCID:PMC5210555. function toggleSingleSummaryText(pn) { var panelNumber = '#collapse' + pn + 'Btn'; var elem = document.querySelector(panelNumber); if (elem.textContent === 'See More') { elem.textContent = 'See Less'; } else { elem.textContent = 'See More'; } }	Informatics at NCATS plays a key role in organizing, processing, analyzing and interpreting translational research data.		About Informatics Research and Scientific Applications in the Division	Informatics at NCATS plays a key role in organizing, processing, analyzing and interpreting translational research data.		About Informatics Research and Scientific Applications in the Division
18270	Development of Acoziborole for the Treatment of Human African Trypanosomiasis	Human African trypanosomiasis (HAT), also known as sleeping sickness, is a life-threatening parasitic disease that is widespread throughout sub-Saharan Africa. HAT spreads through the bite of an infected tsetse fly. In the early stages of infection, parasites in the blood cause mild, nonspecific symptoms. In later stages, the parasites move into the brain, causing severe headaches, disorientation, psychosis, and the characteristic sleep disorders that can lead to coma and death. If left untreated, HAT is fatal. Current treatment varies depending on the stage of infection and requires specialized medical facilities and trained staff, limiting the ability to reach patients in more rural areas. The goal of this project was to develop a single treatment for HAT that is effective in both stages of infection and that will be simpler to dispense, even in resource-limited settings. Scientific Synopsis HAT is transmitted by a vector, the tsetse fly, that introduces trypanosomes — free-living extracellular parasites — into the bloodstream, body fluids, and lymph and cerebrospinal fluid. The Trypanosoma brucei species is pathogenic to humans and endemic to sub-Saharan Africa. T.b. gambiense accounts for more than 98% of cases of HAT (gHAT), and T.b. rhodesiense accounts for about 2% of cases (rHAT). The disease progresses through two stages of infection, first in the blood and lymph and then into the central nervous system (CNS). While in the blood and lymph, clinical signs and symptoms are mild and nonspecific, including headaches, fatigue, and intermittent fevers. By contrast, infection in the CNS is marked by pronounced neuropsychiatric signs, including disrupted sleep/wake cycles, hallucinations and aggression, abnormal reflexes, seizures, and coma. When infection has progressed to the CNS, HAT is more difficult to treat, requiring drugs to cross the blood-brain barrier, making early diagnosis and treatment imperative. Until recently, first-line treatment for late-stage HAT relied on a combination of two drugs (nifurtimox and eflornithine) administered over a course of 10 days, requiring intravenous injection in a clinical setting. To reach wider patient populations in poorer, more remote areas with little health care infrastructure, the lead collaborators developed fexinidazole, an oral therapy taken once daily for 10 days that can treat both early and late stages of infection. To further simplify the treatment regimen, the lead collaborators developed acoziborole, which also treats both stages of infection, but requires only a single oral dose in lieu of a multiday course. Lead Collaborator Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland Laurent Fraisse, Ph.D. Public Health Impact HAT mostly affects poor populations in Africa, typically in remote regions outside of major population centers. Endemic to sub-Saharan Africa, 8.5 million people are estimated to be at risk of HAT infection across 37 countries. Current therapies can be too complex to administer in resource-poor areas without sufficient health infrastructure, and left untreated, HAT infection is fatal. Through this project, TRND has opened the door for DNDi to deliver an effective, easy-to-use treatment for this devastating disease. Outcomes TRND scientists completed Good Laboratory Practice–compliant nonclinical toxicology studies necessary to support the registration of acoziborole with health regulatory authorities to treat HAT patients in Africa. Phase 2/3 trials have concluded and DNDi is moving toward registration, with agreements from the World Health Organization and Sanofi to provide acoziborole for free to patients through their countries’ public health systems.	Human African trypanosomiasis (HAT), also known as sleeping sickness, is a life-threatening parasitic disease that is widespread throughout sub-Saharan Africa.		Development of Acoziborole for the Treatment of HAT	Human African trypanosomiasis (HAT), also known as sleeping sickness, is a life-threatening parasitic disease that is widespread throughout sub-Saharan Africa.		Development of Acoziborole for the Treatment of HAT
18273	A Treatment for Patients with Jansen’s Metaphyseal Chondrodysplasia	Jansen’s metaphyseal chondrodysplasia (JMC) is an ultra-rare disease of skeletal development and mineral ion balance. JMC is caused by mutations in the parathyroid hormone (PTH) receptor, which is present at particularly high levels in growth plates, bones and kidneys. The mutant PTH receptors of JMC are overactive, resulting in bone deformities, extremely short stature and chronic kidney disease, which often requires treatment by dialysis or kidney transplantation later in life. Other complications include premature closure of the spaces between the bones of the skull, leading to damage of cranial nerves and potential vision and hearing loss. Currently, there is no effective treatment for JMC. The lead collaborators have identified a peptide that can reduce the high baseline activity of the mutant PTH receptors. The goal of this project is to complete the preclinical studies necessary to enable clinical trials for JMC. Scientific Synopsis JMC is caused by heterozygous, autosomal-dominant activating mutations in the G protein–coupled PTH receptor type 1 (PTHR1), which is highly expressed in kidney and bone, including the metaphyseal growth plates. PTHR1 signaling plays a role in the formation and long-term physiology of bone. In the kidney, PTH activates the PTHR1, stimulating the reabsorption of calcium and excretion of phosphate and enhancing the generation of biologically active vitamin D; PTHR1 signaling thus acts to balance mineral ions in the blood. In bone, increased PTHR1 signaling stimulates the degradation of the bone matrix and the release of calcium and phosphate into the blood. Constitutive activation of the PTHR1 in JMC leads to marked skeletal abnormalities, including short stature and bowing of the long bones due to hypomineralization, as well as chronic hypercalcemia and hypophosphatemia. The lead collaborators identified the first — and most frequent — PTHR1 mutation of JMC (H223R) and generated a corresponding transgenic mouse model (C1HR) recapitulating some of the JMC skeletal phenotype. They also identified through in vitro studies PTHR1 inverse agonist ligands that can suppress the high basal activity of the mutant receptors causing JMC. These inverse agonists, based on fragments of PTH or the PTH-related protein (PTHrP), then were tested in vivo in the C1HR mouse. One of these PTH inverse agonists (PTH-IA) was found to significantly improve the bone and mineral ion defects in the mutant mice, supporting the hypothesis that a PTH-IA could be developed as a therapy for JMC. Lead Collaborators Massachusetts General Hospital, Boston, MA Thomas Gardella, Ph.D. Harald Jueppner, M.D. John Potts, Jr., M.D. Public Health Impact JMC is an ultra-rare genetic condition, with only about 30 cases identified since its first description in 1934. It is a progressive, debilitating condition with symptoms becoming apparent in early childhood. Patients undergo frequent surgical interventions and intensive physical and occupational therapy to realign bone and mitigate pain. Outcomes TRND scientists have initiated a preclinical development campaign to advance the PTH-IA candidate to clinical evaluation. Planned activities include development of bioanalytical methods, scale-up manufacturing and formulation of the drug product, and the toxicology studies needed to support an Investigational New Drug (IND) application.	Jansen’s metaphyseal chondrodysplasia (JMC) is an ultra-rare disease of skeletal development and mineral ion balance. JMC is caused by mutations in the parathyroid hormone (PTH) receptor.		A Treatment for Patients with Jansen’s Metaphyseal Chondrodysplasia	Jansen’s metaphyseal chondrodysplasia (JMC) is an ultra-rare disease of skeletal development and mineral ion balance. JMC is caused by mutations in the parathyroid hormone (PTH) receptor.		A Treatment for Patients with Jansen’s Metaphyseal Chondrodysplasia
18267	Targeted Bone Regeneration via Activation of Resident Stem Cells	Severe bone fractures constitute a complex medical condition. Between 11 and 15 million bone fractures occur in the United States each year, and up to 12% of these fractures fail to heal with currently available medical strategies. Such fractures result in frequent hospitalizations, multiple surgeries, extended pain and reduced quality of life. The lead collaborators on this project have developed a biological therapy that can regenerate bone without the need for more complex surgical procedures, such as bone grafts and bone transport. This novel therapy recruits the patient’s own stem cells to the fracture site, which are subsequently activated to induce bone regeneration. The goal of this project is to develop the preclinical data necessary to enable first-in-human clinical trials to treat severe bone fractures. Scientific Synopsis More than 1 million severe bone fractures each year fail to heal, resulting in non-union. Current treatments include the use of autografts or bone transport. Limitations associated with autografts — harvesting bone from elsewhere in the patient’s body for use at the site of injury — include the need for an additional surgical procedure with the associated morbidity, increased bleeding and operating room time, acute pain during the procedure, and chronic pain post-implant. Bone transport requires an external circular, modular fixator that is fixed to the broken bone via heavy-gauge wires. The fixator allows partial weight bearing while applying tension to the fractured bone, inducing gradual bone regeneration. Its disadvantages include pain, multiple surgeries, poor patient compliance, inconvenience of the frame, risk of inducing bone malalignment, and a complicated procedure for the surgeon. An alternative approach is the use of bone morphogenetic protein (BMP) to induce bone regeneration. An existing therapy uses BMP-2, but it is used mainly for spinal surgery rather than repair of long bones. Recombinant proteins have short half-lives, requiring large doses that can lead to inflammation and other unwanted side effects. To overcome the limitations of current treatments, the lead collaborators developed a new technology, called SonoHeal, that attracts and activates endogenous tissue stem cells to regenerate bone and heal fractures. First, a biodegradable scaffold is implanted into the fracture site, which recruits the patient’s own mesenchymal stem cells (MSCs). At a second step, BMP-6 plasmid is delivered to the MSCs via sonoporation — the use of transcutaneous ultrasound to transfer plasmid DNA across the cell membrane — resulting in BMP-6 protein expression at a physiological level to induce cell differentiation and promote the formation of new bone and fracture healing. Lead Collaborators Cedars-Sinai Medical Center, Los Angeles, CA Dan Gazit, D.M.D., Ph.D. Gadi Pelled, D.M.D., Ph.D. Public Health Impact More than 1 million severe bone fractures fail to heal each year in the United States, and most long bone fractures occur in people younger than 50 years of age. In addition to the chronic pain and reduced quality of life for patients, a substantial burden of related medical costs is associated with fracture repair, as well as disability and lost work productivity of the working-age population and their employers. Outcomes BrIDGs scientists have initiated a preclinical development campaign to advance the SonoHeal technology to clinical evaluation. Planned activities include development of bioanalytical methods, in vivo efficacy and biodistribution studies, manufacture and characterization of the injectable drug product, and the toxicology studies needed to support an Investigational New Drug application.	More than 1 million severe bone fractures each year fail to heal, resulting in non-union. Current treatments include the use of autografts or bone transport.		Targeted Bone Regeneration via Activation of Resident Stem Cells	More than 1 million severe bone fractures each year fail to heal, resulting in non-union. Current treatments include the use of autografts or bone transport.		Targeted Bone Regeneration via Activation of Resident Stem Cells
18225	Informatics Scientists and Software Developers (old)	.row.odd{ background-color: #f6f6f6; } .row{ margin-bottom:20px; } .img-responsive{ margin-top:15px; margin-bottom:15px; } p.title { font-weight: 600; } Informatics scientists and software developers play a crucial role in NCATS translational programs and work closely with experts in other biomedical and translational research fields (biology, chemistry, epidemiology, biostatistics, etc.) within and outside NCATS. Collectively, they address the full breadth of translational science challenges, including drug development and repurposing, development of model systems for drug and toxicity screening, and development of comprehensive and state-of-the-art software, resources and analytical tools. To meet these broad demands, NCATS’ informatics scientists and software developers work cross-functionally and have a wide array of expertise. Learn more about our: Bioinformaticians Cheminformaticians Developers Project and Program Managers Regulatory Science Fellow Bioinformaticians John Braisted, B.S. Informatics Scientist/Engineer John received a B.S. in zoology in 1983 from the University of Maryland, College Park (UMCP), with a focus on human physiology and biochemistry. He applied this degree in basic and applied research at the Naval Medical Research Institute studying free radical mechanisms of toxicity and relevance to hyperbaric oxygen treatment. John then received a B.S. degree in computer science in 2002 from UMCP with a focus on software engineering algorithms and computational analysis. He worked for 10 years as a software engineer and software engineer manager at The Institute for Genomic Research (TIGR), which later became the J. Craig Venter Institute (JCVI), where his work focused on developing tools for omics analysis. John joined NCATS in 2012 in a combination role of software developer and data scientist on multi-omics and small-molecule high-throughput screening projects. Lu Chen, Ph.D. Informatics Scientist Lu is the informatics leader of the Functional Genomics Laboratory at NCATS. He leads a team that collaborates with the NIH intramural research community to improve functional genomics (RNAi and CRISPR-Cas9) screening approaches for better understanding gene function and identifying biologically relevant targets. He is dedicated to developing high-throughput RNAi/CRISPR-Cas9 screening platforms, promoting data sharing and robust statistical tools, such as siRNA off-target analysis. In 2020, he participated in a drug combination repurposing campaign as part of NCATS’ efforts to address the COVID-19 pandemic. Lu has a B.S. in biological sciences from Fudan University (2009) and a Ph.D. in experimental therapeutics from the University of Texas Health Science Center at Houston (2015). Staff profile Tara Eicher, M.S. Graduate Partnership Program Trainee Tara received her B.A. in mathematics and her M.S. in computer science from Wichita State University, and she is pursuing a Ph.D. from The Ohio State University. Her prior projects in bioinformatics include modeling associations between the proteome and genome in breast and ovarian cancer and predicting regulatory elements in the epigenome using chromatin accessibility data. Currently, Tara is leveraging graph theory and ML approaches to understand the biological pathways involved in asthma and COVID-19. Xin Hu, Ph.D. Informatics Lead, NIH HEAL Initiative Xin received a B.S. in pharmaceutical sciences at the Peking University School of Pharmacy and a Ph.D. in pharmaceutical sciences at North Dakota State University. He was trained in bioinformatics and computational biology as a postdoctoral fellow at Rockefeller University. Before joining NCATS in 2010, he served as a research scientist at the Biotechnology High Performance Computing Software Applications Institute at the Department of Defense, where he worked on development of computational approaches for structure-based drug design. Xin’s current research at NCATS focuses on the Helping to End Addiction Long-termSM Initiative, or NIH HEAL InitiativeSM, where he works closely with biologists and chemists and leads the informatics efforts to develop new therapeutics and drugs for pain, addiction and overdose. Staff profile Jason Inman, M.S. Bioinformatics Scientist Jason analyzes single-cell and bulk genetic data and contributes expertise in pipeline building and scripting as warranted by the needs of NCATS. Before joining NCATS, Jason was at The Institute for Genomic Research, which later became the J. Craig Venter Institute, for 14 years and was involved in many aspects of genomic research, including genome assembly; annotation of eukaryotic, prokaryotic, and viral genomes; pan-genomic and metagenomic analysis; and general data support. Prior to that, Jason spent six years in the National Institute of Mental Health’s Laboratory of Genetics, in both wet-lab and informatics capacities. Jason received both his M.S. in biotechnology (2002) and M.S. in bioinformatics (2011) from Johns Hopkins University. He received his B.S. in integrated science and technology from James Madison University in 1999. Claire Malley, M.S. Research Collaborator and Former Bioinformatics Scientist, Stem Cell Translation Lab Claire currently is a statistician at the National Eye Institute working in genetic epidemiology. She led bioinformatics analysis of next-generation sequencing data for biologists in the Stem Cell Translation Laboratory (SCTL), developed an RShiny app (iPSCeq) for storage and interaction with bulk and single-cell RNA-Seq data from the laboratory, and developed the iPSC Portal website for the group. She received a B.S. in ecology and evolutionary biology from the University of Michigan and an M.S. in plant biology with a focus on bioinformatics from Northwestern University. She currently is a part-time Ph.D. student in bioinformatics and computational biology at George Mason University and continues to collaborate with the SCTL and Informatics on projects. Staff profile Ewy Mathé, Ph.D., Director of Informatics Core Ewy received her B.S. in biochemistry from Mount Saint Mary’s University in 2000 and a Ph.D. in bioinformatics from George Mason University in 2006. During her postdoctoral training with Curtis Harris, M.D., at the National Cancer Institute, she discovered putative esophageal and lung cancer biomarkers using miRNA microarrays and metabolomics. As a bioinformatics staff scientist in the laboratory of Rafael Casellas, Ph.D., at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, she studied modalities of transcriptional regulation in B lymphocytes, using state-of-the-art next-generation sequencing techniques. She later took a faculty appointment in the Biomedical Informatics Department at The Ohio State University and built a research program developing algorithms for biomarker and therapeutic target discovery in cancer. She joined NCATS as director of informatics in 2020 and is leading a talented and diverse team of experts with the common vision of empowering translational research using state-of-the-art informatics technologies. Staff profile Andrew Patt, B.Sc. Research Associate (Graduate Student) Andrew received his B.Sc. in biochemistry/biomathematics from the State University of New York College at Geneseo in 2015. From 2015 to 2016, he was a postbaccalaureate fellow working with Michael Ombrello, M.D., at the National Institute of Arthritis and Musculoskeletal and Skin Diseases to identify ultra-rare genetic variants associated with systemic juvenile idiopathic arthritis. In 2016, he began working with Ewy Mathe, Ph.D., at The Ohio State University while pursuing a Ph.D. in biomedical informatics, and he transitioned to NCATS in 2020. His research interests include metabolomics and bioinformatics. His projects include the identification of metabolomic profiles associated with worse dedifferentiated liposarcoma, development of the Relational Database of Metabolomics Pathways (RaMP) database/R package, and development of network-based methodology for functional enrichment analysis of metabolomic data. Kyle Spencer, M.S. Graduate Partnership Program Trainee Kyle received his B.S. in biomedical sciences in 2016 and an M.S. in biology in 2018 from Central Michigan University, and he is pursuing a Ph.D. in biomedical sciences focusing on computational biology and bioinformatics at The Ohio State University. Kyle’s current projects seek to understand how diet affects the composition of the bacteriome and metabolome in the gut and, ultimately, how it affects gut epithelial integrity. Kyle’s goal is to merge classical bacteriology with the power of computational biology to improve digestive health. Gregory Tawa, Ph.D. Staff Scientist Gregory received his Ph.D. in chemical physics from New York University in 1990, where he studied the quantum mechanics of small molecules. He then performed postdoctoral work at the University of Minnesota, where his research focused on the dynamics of atom-molecule scattering. Since then, his work has gravitated toward life sciences and human health. Gregory spent 10 years in industry performing computational drug design and cheminformatics. He spent eight years at Wyeth Pharmaceuticals, where he was a key member of multiple drug discovery projects, ranging from the very early exploratory stages to the actual development phase. At Wyeth, he gained intimate familiarity with the computational aspects of drug discovery. In 2014, Gregory joined NCATS, where he headed the Modeling and Informatics for the Therapeutic Development Branch (TDB). In addition to supporting TDB’s computational needs, Gregory also leads multiple projects that focus on bioinformatics-driven comparative canine-human oncology. Staff profile Cheminformaticians Ruili Huang, Ph.D. Informatics Team Lead Ruili received her Ph.D. in chemistry from Iowa State University, working on chemical kinetics and mechanisms for reactions catalyzed by organometallic compounds. She came to NCATS in 2006 from the National Cancer Institute, where she was a computational biologist working on deconvoluting biochemical pathways and drug-gene-pathway relationships. Ruili is the informatics team leader on the toxicity profiling team at NCATS and the co-chair of the chemical library working group of the Toxicology in the 21st Century (Tox21) initiative. Staff profile Sankalp Jain, Ph.D. Postdoctoral Fellow Sankalp completed his B.Tech. in bioinformatics from the Jaypee University of Information Technology, India, in 2010, followed by a Master’s degree in life science informatics at the University of Bonn, Germany, in 2013. Pursuing his interest in the field of computational drug design, he received a doctorate in pharmacoinformatics from the University of Vienna, Austria, in 2018. Sankalp’s current research focuses on the application and development of in silico classification and prediction models to predict bioactivity for small molecules and virtual screening approaches to accelerate the drug development process. As a member of the Adenine Team and a computational chemist, he specializes in applying cheminformatics, ML and molecular modeling to translational science projects. Staff profile Abhijeet Kapoor, Ph.D. Informatics Scientist Abhijeet received a B.Tech. in bioinformatics from the Jaypee University of Information Technology, India, in 2008, and a Ph.D. in bioinformatics and computational biology at Iowa State University in 2014. His postdoctoral work in the laboratory of Marta Filizola, Ph.D., at the Icahn School of Medicine at Mount Sinai focused on using enhanced sampling molecular dynamics methods to elucidate the thermodynamic and kinetic elements of ligand-induced dynamics of the μ-opioid receptor, a target of opioid painkillers. He also worked on early discovery projects involving different classes of proteins (ion channels, transcription factors, etc.), during which he conducted hit identification and lead optimization protocols. Abhijeet joined NCATS in 2020 as an informatics scientist. Currently, he is involved in early discovery projects using structure-based approaches to identify small-molecule probes that disrupt or promote protein-protein interactions to restore cellular and tissue homeostasis. Ðắc-Trung Nguyễn, M.S. Cheminformatician and Senior Software Architect Ðắc-Trung received a B.S. in Electrical Engineering from the University of Maryland, College Park and an M.S. in Computer Science from the Johns Hopkins University. Ðắc-Trung contributed as an active member of the engineering team behind the first draft assembly of the human genome (2000) with two decades of experience building infrastructure for therapeutic discovery, first at Celera Genomics and later at NIH, starting in 2007. He is the lead scientist from NCATS contributing to the Illuminating the Druggable Genome program and the Genetic and Rare Diseases Information Center (GARD), and he is responsible for the development of the Pharos website. Mohsen Pourmousa, Ph.D. Informatics Scientist Mohsen joined NCATS in 2019 as a scientist in the Informatics Core within the Division of Preclinical Innovation. He received his B.Sc. in physics from Sharif University of Technology and his M.Sc. in physics from the Institute for Advanced Studies in Basic Sciences, both in Iran, and his Ph.D. in computational biophysics from the University of Western Ontario in Canada. Prior to joining NCATS, he was a postdoctoral fellow at Tampere University of Technology in Finland and a research fellow at the Laboratory of Computational Biology at the National Heart, Lung, and Blood Institute. He analyzes quantitative high-throughput screening data to identify hits and employs structure- and ligand-based modeling techniques to inform the medicinal chemistry efforts in the hit-to-lead and lead optimization process. His computational skills include docking, molecular dynamics simulation, free energy calculation, quantitative structure-activity relationship and ML. Min Shen, Ph.D. Informatics Group Lead, Early Translational Branch Min received her Ph.D. in computational chemistry at the University of North Carolina at Chapel Hill. She also holds a B.S. in pharmaceutical sciences from the Peking University School of Pharmacy in China. She has diverse expertise in database mining, high-throughput virtual screening, lead identification and optimization using both small molecule–based and protein structure–based computational approaches. Staff profile Vishal Siramshetty, Ph.D. Postdoctoral Fellow Vishal received a B.S. in pharmacy from Osmania University in India in 2010 and an M.Sc. in life science informatics from the University of Bonn in Germany in 2014. In 2018, he received a doctoral degree in cheminformatics from Freie Universität Berlin in Germany. Vishal’s current research focuses on the development of computational prediction models for pharmacological endpoints, formulation of informatics approaches for illumination of understudied protein targets of the human genome, and dissemination of cheminformatics tools through such data analytics platforms as KNIME. He actively collaborates with the absorption, distribution, metabolism, and excretion (ADME) group on the development of predictive models and exploration of the structure-metabolism data. Noel Southall, Ph.D. Informatics Team Lead Noel holds a Ph.D. in biophysics from the University of California, San Francisco, which he received in 2001. He develops software and standards, and he provides data science analysis for therapeutic project teams, from interpreting high-throughput screening data to bioinformatics and structure-based modeling to biomarker discovery and development. His current research focuses on early therapeutic discovery and drug repurposing. As the informatics lead in the Thymine Team in the Early Translation Branch, he works as a computational chemist, specializing in cheminformatics and molecular modeling. He has 15 years’ experience providing informatics leadership for discovery teams and software development projects, and he served as the Division of Preclinical Innovation’s acting director of Informatics in 2019. Hongmao Sun, Ph.D. Informatician Hongmao received his Ph.D. in computational and medicinal chemistry at Clark University and the University of Massachusetts Medical School. He also received a Ph.D. in physics at the University of Science and Technology of China (USTC) and a B.S. in chemistry from USTC. He received postdoctoral training in the laboratory of Garland Marshall, Ph.D., at the Washington University School of Medicine in St. Louis. He has 10 years of industry experience on rational drug design with Hoffmann-La Roche. Before joining NCATS in 2011, he worked for the U.S. Department of Defense’s Biotechnology High Performance Computing Software Applications Institute for one year. Hongmao published a monograph, A Practical Guide to Rational Drug Design, with Elsevier in 2015. Staff profile Yuhong Wang, M.S. Informatics Scientist/Engineer Yuhong holds a Master’s degree in bioorganic chemistry from Shanghai Institute of Organic Chemistry, China, which he received in 1987. He develops both algorithms and software for high-throughput data analysis and drug design. His current research focuses on new computational algorithms for structural modeling and drug design, using both traditional and ML algorithms. Staff profile Gergely Zahoránszky-Kőhalmi, Ph.D. Postdoctoral FellowInformatics Lead, ASPIRE Gergely’s research in the ASPIRE program at NCATS focuses on chemistry automation and the design and synthesis of novel bioactive molecules. He developed reaction informatics methods using AI/ML technologies involving network theory, machine learning and deep learning. He also is responsible for coordinating informatics research and development projects in ASPIRE. Before joining NCATS, he was a development engineer at Sanofi and a synthesis leader chemist at AMRI, Inc. He received his Ph.D. in the field of biomedical sciences at the University of New Mexico School of Medicine, where he was also a visiting Fulbright Scholar in 2010–2011. Staff profile Alexey Zakharov, Ph.D., M.D. Informatics Group Leader, Early Translational Branch Alexey graduated with a Master’s degree in biochemistry from the Russian State Medical University, Moscow, Russia, in 2005. He received his doctorate in bioinformatics from the Institute of Biomedical Chemistry of the Russian Academy of Medical Sciences in 2008. Alexey’s group’s research is based on the strong overlap between different scientific fields, including bioinformatics, cheminformatics, biochemistry, computational chemistry and toxicology, statistics, and AI/ML. Staff profile Qian Zhu, Ph.D. Informatics Scientist Qian joined the NCATS informatics group in 2018 and currently works on the Genetic and Rare Diseases Information Center (GARD) in supporting the development of GARD 2.0. She also manages activities conducted by multiple clinical data groups and coordinates their effort through the Biomedical Data Translator consortium and designs and develops AI-based retrosynthesis applications to support automated synthesis for ASPIRE projects. Before joining NCATS, Qian, was a faculty member in the Department of Informatics Systems at the University of Maryland, Baltimore County and a senior research scientist II in the Division of Public Health at Social & Scientific Systems, Inc., where she directed AI and natural language processing–based automated placenta data curation for the Placenta Atlas Tool, which was funded by the Eunice Kennedy Shriver National Institute for Child and Human Development. She earned her Ph.D. in cheminformatics from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, in China. She was a research associate at Indiana University, working with scientists from the Eli Lilly and Company to develop computational programs for drug discovery. Working under the supervision of Christopher G. Chute, M.D., Dr.P.H., FACMI, she was trained as a professional biomedical informatician at the Mayo Clinic, working with a large volume of patient data. Developers Zarina Dizmang, M.A UIUX Designer Zarina works in the informatics group with NCATS on CURE ID, a collaborative project with the U.S. Food and Drug Administration. Zarina holds a Master's Degree in Arts from Taraz State University of Technology and has been working in web development for the past three years. Ruby Geng, M.S. Software Engineer Ruby works in the informatics group with NCATS working on the collaborative CURE ID project with the U.S. Food and Drug Administration. Ruby holds an M.S. in computer science from the Xian Institute of Technology University. Serghei Gorobet Full Stack Developer Serghei is a full stack developer who works with the U.S. Food and Drug Administration to develop CURE ID. Serghei believes that CURE ID is a very useful tool, especially today, and that it can offer significant help to the public in discovering new uses for drugs. Hui Guo, M.S. Informatics Analyst Hui received a Master's degree in civil engineering from University of California, Davis and a B.S. in computer science from Qingdao University of Science and Technology in China. Hui works on data analysis to support early discovery activities in DPI. He is involved in supporting the NIH HEAL Initiative. Hui also works on matrix data analysis to support the Matrix Combination Screening program. Danny Katzel, B.S. Senior Software Engineer Danny received his B.S. in computer science from The George Washington University. After graduation, he worked at The Institute for Genomic Research, which later became the J. Craig Venter Institute. He currently works on the Global Substance Registration System (G-SRS) project and developed Molwitch, which allows NCATS software to toggle between cheminformatics libraries — such as JChem, CDK and Indigo — without any recompilation. Keith Kelleher, Ph.D. Senior Full Stack Developer Keith received a B.S. in psychology from Florida State University and a Ph.D. in neuroscience from the University of Houston. More recently, he worked as a software developer at Epic in Verona, Wisconsin. Currently, he works on the full development stack for Pharos. Xiaoyu (Shawn) Li, B.S. Full-stack Developer Shawn works in the informatics group on the COVID-19 OpenData portal. Shawn holds a bachelor's degree in computer science from University of California, Irvine. Marissel Llavore, M.S., HCI/d UX Researcher Specialist Marissel works in the informatics group on Pharos and the COVID-19 OpenData Portal projects. She holds an M.S. in human computer interaction/design from Indiana University, Bloomington. Mitch Miller, Ph.D. Developer Mitch received a B.A. in comparative literature from Queens College and a Ph.D. in chemistry from the City University of New York during the latter part of the last century. Currently, he is working on Global Substance Registration System (G-SRS), where he is assisting with server development and testing, creating an Excel add-in for G-SRS and providing customer support, and Resolver, including creating an Excel add-in for Resolver. He is comfortable programming in both Java and C#. Jorge Neyra, B.S. Developer Jorge received a B.S. in international business with a minor in computing from the University of Maryland University College and currently is working on a Master’s in data science at the University of Maryland, Baltimore County. At NCATS, he has helped develop the user interface for the Global Substance Registration System (G-SRS) and is currently working on the Relational Database of Metabolomics Pathways (RaMP) database. Timothy Sheils, B.S. Senior Web Applications Developer Tim received a B.A. in philosophy in 2005 from the University of Maryland, Baltimore County and a B.S. in computer science in 2013 from the University of Maryland University College. He currently works on front-end interfaces for Pharos, CURE ID and Genetic and Rare Diseases Information Center (GARD). His favorite technologies to work with are Angular, Neo4j and D3 visualizations. Staff profile Mark Williams, B.S. Software Engineer Mark received a B.S. in computer science from the University of South Carolina. He currently works on the Biomedical Data Translator as a software engineer and technical liaison. His focus is on integrating previously disparate biomedical data to allow meaningful cross-domain querying. Lin Ye, Ph.D. Informatics Scientist Lin joined NCATS in 2018 as a postdoctoral researcher. She analyzes quantitative high-throughput screening data and builds predictive models for in vivo toxicity endpoints for Tox21 working groups. Before joining NCATS, Lin worked in the U.S. Food and Drug Administration (FDA) Center for Food Safety and Applied Nutrition, where she participated in the development of the Chemical Evaluation and Risk Estimation System. Prior to her fellowship at FDA, Lin was a postdoctoral researcher in the School of Pharmacy at the University of North Carolina at Chapel Hill, where she worked on developing QSAR model for toxicity endpoints. Lin received her Ph.D. in chemistry from the University of Missouri–Kansas City, where her work focused on modeling of polymer-based dental restorative materials. Tongan Zhao, M.S. Senior Web Application Developer Tongan received his B.S. in chemical engineering from the Zhengzhou University in China and an M.S. in computer science at the University of Missouri–Kansas City. He currently works on full-stack development of the Tox21 Gateway and COVID-19 OpenData Portal. His work focuses on full-stack web application development, data management and application programming interface development. Project and Program Managers Poorva Dharkar, Ph.D., M.B.A. Program Manager Poorva joined the informatics group as a program manager in May 2020, where she manages the DPI informatics program by providing program management to the Informatics Core. She also provides project management for COVID-19 OpenData portal, Genetic and Rare Diseases Information Center (GARD), Relational Database of Metabolomics Pathways (RaMP) and Omics 3-D model for DPI’s informatics group. Poorva earned her Ph.D. in biotechnology from the University of Pune, India, in the National Chemical Laboratory. She did her postdoctoral fellowship at the National Cancer Institute and later at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, using protein crystallography to focus on cancer and neuroscience. Sarah Stemann, M.S. Project Manager Sarah is the project manager for the Global Substance Registration System (G-SRS) and Biomedical Data Translator programs for the informatics group. She works closely with software developers, lead investigators, program managers and web design teams to align work streams and apply a consistent project management approach. For G-SRS, she provides support for a critical collaboration with the U.S. Food and Drug Administration, guiding the development team toward clear deliverables and ensuring the production releases of software at the agency. Sarah received a B.S. in business information technology from the Virginia Polytechnic Institute and State University (Virginia Tech) in 2003. Regulatory Science Fellow Parvesh Paul, M.D. ORISE Fellow Parvesh is a medical doctor with 10 years’ experience working in both rural and tertiary hospital settings in India. He currently is working on CURE ID, a joint U.S. Food and Drug Administration–NCATS infectious diseases project. He is involved with the medical aspects of development of the project and is devoted to achieving positive patient outcomes and remaining abreast of the most recent advances in medical evidence. He specialized in internal medicine during his residency, with significant exposure to the management of infectious diseases and critical care with a sub-focus on neurology.			Informatics Scientists and Software Developers	Informatics scientists and software developers at NCATS have a wide array of expertise to address translational science challenges.		Informatics Scientists and Software Developers
18264	Development of Drinabant for Treatment of Acute Cannabinoid Overdose	The leaves and flowers of the cannabis plant contain tetrahydrocannabinol (THC), the compound in marijuana that produces a “high” when smoked. In addition to the natural THC found in marijuana, synthetic cannabinoid (SC) compounds also produce a high when consumed. SCs and cannabis leaves and extracts also can be mixed into foods and beverages (edibles). Cannabis extracts are enriched in THC, and SCs can be much more potent than THC itself. These edibles can deliver extremely large amounts of THC and SCs to the body through overconsumption. THC and SCs act in the brain by binding to the cannabinoid receptor. In acute cannabinoid overdose, excessive THC/SCs can cause anxiety, paranoia, visual and auditory hallucinations, and nausea. In some cases, these symptoms are severe enough to require emergency medical attention. Drinabant binds to the same brain receptor as THC/SCs and can be administered to block their activity during an acute overdose. The goal of this project is to develop the preclinical data and clinical materials necessary to enable clinical trials to treat acute cannabinoid overdose. Scientific Synopsis Acute cannabinoid overdose (ACO) results from the consumption of large quantities of cannabinoid compounds. These include delta-9-THC, the naturally occurring psychoactive compound in cannabis plants, as well as other SC compounds. Although SCs are chemically distinct from THC, THC and SCs elicit psychoactive effects through the binding and activation of cannabinoid (CB) receptors in the brain, principally the CB-1 receptor. Initially developed as research tools to study CB receptors, SCs are reported to be more potent and efficacious than THC at activating CB-1 receptors. A critical issue with edibles is that absorption of the THC/SC through the gut is delayed compared to smoking. The subsequent delay in the onset of a high leads some to overconsume these edibles. Because it can be difficult to gauge how much THC/SC is contained in an individual edible, this overconsumption can quickly result in an overdose. Symptoms of ACO have been reported to last anywhere from several hours to days, leading some individuals to require emergency medical attention or even hospitalization. Individuals using SCs are about 30 times more likely to require emergency medical care than those smoking marijuana. The therapeutic hypothesis is that a CB-1 antagonist can reverse the clinical manifestations of ACO by replacing the agonist (THC or SC) bound to CB-1 receptors. Prior clinical studies have demonstrated that oral administration of CB-1 antagonists (drinabant, surinabant) can block the pharmacodynamic effects of inhaled THC. Orally administered drinabant has a slow onset, making it impractical to administer in the acute overdose setting. To improve the pharmacokinetics, the lead collaborators have proposed a parenteral route of administration (intravenous or intramuscular injection) that would be more amenable to treating ACO in the emergency medical setting. Lead Collaborator Opiant Pharmaceuticals, Santa Monica, CA Phil Skolnick, Ph.D., D.Sc. (hon.) Public Health Impact The risks of ACO are increased by the consumption of synthetics and edibles, because it is difficult to know how much THC or other SC is present in foods and beverages. If symptoms drive a patient to seek medical care, no FDA-approved medications exist to treat ACO. Emergency medicine departments can only manage symptoms, which in the severest cases could require longer hospitalization. Outcomes BrIDGs scientists have initiated a preclinical development campaign to advance drinabant to clinical evaluation. Planned activities include development of an injectable formulation and the pharmacokinetic and toxicology studies needed to support an Investigational New Drug application.	Acute cannabinoid overdose (ACO) results from the consumption of large quantities of cannabinoid compounds.		Development of Drinabant for Treatment of Acute Cannabinoid Overdose	Acute cannabinoid overdose (ACO) results from the consumption of large quantities of cannabinoid compounds.		Development of Drinabant for Treatment of Acute Cannabinoid Overdose
18222	Publications (old)	See publications from: 2020 2019 2018 and earlier Some publications may require a subscription to access full manuscripts. Featured Publications Brimacombe KR, Zhao T, Eastman RT, et al. An OpenData portal to share COVID-19 drug repurposing data in real time. bioRxiv. Preprint posted online June 5, 2020:2020.06.04.135046. doi:10.1101/2020.06.04.135046. PMID:32511420. PMCID:PMC7276055. Sheils T, Mathias S, Kelleher K, et al. TCRD and Pharos 2020: Mining the human proteome for disease biology. Nucleic Acids Res. Forthcoming. Zhao Y, Man-Un Ung P, Zahoránszky-Kőhalmi G, et al. Identification of a G-protein-independent activator of GIRK channels. Cell Rep. 2020;31(11):2211-1247. doi:10.1016/j.celrep.2020.107770. 2020 Brimacombe KR, Zhao T, Eastman RT, et al. An OpenData portal to share COVID-19 drug repurposing data in real time. bioRxiv. Preprint posted online June 5, 2020:2020.06.04.135046. doi:10.1101/2020.06.04.135046. PMID:32511420. PMCID:PMC7276055. Chu PH, Chen G, Kuo D, et al. Stem cell-derived endothelial cell model that responds to tobacco smoke like primary endothelial cells. Chem Res Toxicol. 2020;33(3):751-763. doi:10.1021/acs.chemrestox.9b00363. PMID:32119531. Eicher T, Kinnebrew G, Patt A, et al. Metabolomics and multi-omics integration: A survey of computational methods and resources. Metabolites. 2020;10(5):202. doi:10.3390/metabo10050202. PMID:32429287. PMCID:PMC7281435. Ellis CR, Racz R, Kruhlak NL, et al. Evaluating kratom alkaloids using PHASE. PLoS One. 2020;15(3):e0229646. doi:10.1371/journal.pone.0229646. eCollection 2020. PMID:32126112. Godfrey AG, Michael SG, Sittampalam GS, Zahoránszky-Köhalmi G. A perspective on innovating the chemistry lab bench. Front Robot AI. 2020;7:24. doi:10.3389/frobt.2020.00024. Patt A, Demoret B, Stets C, et al. MDM2-dependent rewiring of metabolomic and lipidomic profiles in dedifferentiated liposarcoma models. Cancers (Basel). 2020;12(8):2157. doi:10.3390/cancers12082157. PMID:32759684. PMCID:PMC7463633. Peryea, T, Southall, N, Miller, M, et al. Global Substance Registration System: consistent scientific descriptions for substances related to health. Nucleic Acids Res. Epub November 2, 2020. doi:doi.org/10.1093/nar/gkaa962. PMID:33137173. Shah P, Siramshetty VB, Zakharov AV, Southall NT, Xu X, Nguyen DT. Predicting liver cytosol stability of small molecules. J Cheminform. 2020;12:21. doi:10.1186/s13321-020-00426-7. PMCID:PMC7140498. Sheils T, Mathias S, Kelleher K, et al. TCRD and Pharos 2020: Mining the human proteome for disease biology. Nucleic Acids Res. Forthcoming. Sheils T, Mathias SL, Siramshetty VB, et al. How to illuminate the druggable genome using Pharos. Curr Protoc Bioinformatics. 2020;69(1):e92. doi:10.1002/cpbi.92. PMID:31898878. Siramshetty VB, Nguyen DT, Martinez NJ, Simeonov A, Southall NT, Zakharov A. Critical assessment of artificial intelligence methods for prediction of hERG channel inhibition in the “big data” era. ChemRxiv. Epub April 16, 2020. doi:10.26434/chemrxiv.12119040.v1. Tong ZB, Braisted J, Chu PH, Gerhold D. The MT1G gene in LUHMES neurons is a sensitive biomarker of neurotoxicity. Neurotox Res. Epub September 1, 2020. doi:10.1007/s12640-020-00272-3. PMID:32870474. Tristan CA, Ormanoglu P, Slamecka J, et al. Robotic high-throughput biomanufacturing and functional differentiation of human pluripotent stem cells. bioRxiv. Preprint posted online August 3, 2020:2020.08.03.235242. doi:10.1101/2020.08.03.235242. PMID:32793899. PMCID:PMC7418713. Zahoránszky-Kőhalmi G, Sheils T, Oprea TI. SmartGraph: A network pharmacology investigation platform. J Cheminform. 2020;12:5. doi:10.1186/s13321-020-0409-9. Zahoranszky-Kohalmi G, Wan KK, Godfrey AG. (2020): Hilbert-curve assisted structure embedding method. ChemRxiv. Preprint posted online February 28, 2020. doi:10.26434/chemrxiv.11911296.v1. Zhao Y, Man-Un Ung P, Zahoránszky-Kőhalmi G, et al. Identification of a G-protein-independent activator of GIRK channels. Cell Rep. 2020;31(11):2211-1247. doi:10.1016/j.celrep.2020.107770. Zhu Q, Nguyen DT, Alyea G, Hanson K, Sid E, Pariser A. Phenotypically similar rare disease identification from an integrative knowledge graph for data harmonization: Preliminary study. JMIR Med Inform. 2020;8(10):e18395. doi:10.2196/18395. PMID:33006565. Zhu Q, Nguyen DT, Sid E, Pariser A. Leveraging the UMLS as a data standard for rare disease data normalization and harmonization. Methods Inf Med. In Press. 2019 Austin CP, Colvis CM, Southall NT. Deconstructing the translational Tower of Babel. Clin Transl Sci. 2019;12(2):85. doi:10.1111/cts.12595. Epub 2018 Nov 9. PMID:30412342. Chen Y, Tristan CA, Chen L, et al. A versatile polypharmacology platform promotes cytoprotection and viability of human pluripotent and differentiated cells. bioRxiv. Preprint posted online October 22, 2019. doi:10.1101/815761. Fecho K, Ahalt SC, Arunachalam S, et al.; Biomedical Data Translator Consortium. Sex, obesity, diabetes, and exposure to particulate matter among patients with severe asthma: Scientific insights from a comparative analysis of open clinical data sources during a five-day hackathon. J Biomed Inform. 2019;100:103325. doi:10.1016/j.jbi.2019.103325. PMID:31676459. PMCID:PMC6953386. Gorshkov K, Chen CZ, Marshall RE, et al. Advancing precision medicine with personalized drug screening. Drug Discov Today. 2019;24(1):272-278. doi:10.1016/j.drudis.2018.08.010. PMID:30125678. Huang R, Grishagin I, Wang Y, et al. The NCATS BioPlanet — An integrated platform for exploring the universe of cellular signaling pathways for toxicology, systems biology, and chemical genomics. Front Pharmacol. 2019;10:445. doi:10.3389/fphar.2019.00445. eCollection 2019. PMID:31133849. Huang R, Zhu H, Shinn P, et al. The NCATS Pharmaceutical Collection: A 10-year update. Drug Discov Today. 2019;24(12):2341-2349. doi:10.1016/j.drudis.2019.09.019. PMID:31585169. Peryea T, Katzel D, Zhao T, Southall N, Nguyen DT. MOLVEC: Open source library for chemical structure recognition. In Abstracts of Papers of the American Chemical Society. Vol. 258. Washington, D.C.: American Chemical Society; 2019. Solinski HJ, Dranchak P, Oliphant E, et al. Inhibition of natriuretic peptide receptor 1 reduces itch in mice. Sci Transl Med. 2019;11(500):eaav5464. doi:10.1126/scitranslmed.aav5464. PMID:31292265. PMCID:PMC7218920. Southall NT, Natarajan M, Lau LPL, et al.; IRDiRC Data Mining and Repurposing Task Force. The use or generation of biomedical data and existing medicines to discover and establish new treatments for patients with rare diseases — recommendations of the IRDiRC Data Mining and Repurposing Task Force. Orphanet J Rare Dis. 2019;14(1):225. doi:10.1186/s13023-019-1193-3. PMID:31615551. Southall NT. Freedom of Information Act access to an investigational new drug application. ACS Pharmacol Transl Sci. 2019;2(6):497-500. doi:10.1021/acsptsci.9b00056. eCollection 2019 Dec 13. PMID:32259081. Zakharov AV, Zhao T, Nguyen DT, et al. Novel consensus architecture to improve performance of large-scale multitask deep learning QSAR models. J Chem Inf Model. 2019;59(11):4613-4624. doi:10.1021/acs.jcim.9b00526. PMID:31584270. 2018 and Earlier Coussens NP, Braisted JC, Peryea T, Sittampalam GS, Simeonov A, Hall MD. Small-molecule screens: A gateway to cancer therapeutic agents with case studies of Food and Drug Administration–approved drugs. Pharmacol Rev. 2017;69(4):479-496. doi:10.1124/pr.117.013755. PMID:28931623. PMCID:PMC5612261. Kearney SE, Zahoránszky-Kőhalmi G, Brimacombe KR, et al. Canvass: A crowd-sourced, natural-product screening library for exploring biological space. ACS Central Science. 2018;4(12):1727-1741. doi:10.1021/acscentsci.8b00747. PMID:30648156. Nguyen DT, Mathias S, Bologa C, et al. Pharos: Collating protein information to shed light on the druggable genome. Nucleic Acids Res. 2017;45(D1):D995-D1002. doi:10.1093/nar/gkw1072. PMID:27903890. PMCID:PMC5210555. Oprea TI, Bologa CG, Brunak S, et al. Unexplored therapeutic opportunities in the human genome. Nat Rev Drug Discov. 2018;17(5):317-332. doi:10.1038/nrd.2018.14. PMID:29472638. Tong ZB, Huang R, Wang Y, et al. The Toxmatrix: Chemo-genomic profiling identifies interactions that reveal mechanisms of toxicity. Chem Res Toxicol. 2018;31(2):127-136. doi:10.1021/acs.chemrestox.7b00290. PMID:29156121. Zhou W, Sun W, Yung MMH, et al. Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance. Oncogene. 2018;37(29):3981-3997. doi:10.1038/s41388-018-0238-8. PMID:29662190. PMCID:PMC6054535.			Publications			Publications

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