Assay Guidance Workshop for High-Throughput Screening and Lead Discovery
This two-day virtual workshop hosted by NCATS Assay Guidance Manual (AGM) covered a broad range of critical concepts underlying assay development and implementation for high-throughput screening and lead discovery projects. This workshop was designed to disseminate best practices for the development and implementation of robust assay methods. It is particularly relevant for researchers developing molecular probes or clinical candidates. Many of the workshop instructors have 20 to 30 years of experience in the field of drug discovery and share information not readily found in a classroom or published material outside of the AGM. This workshop also covered emerging technologies and modalities in drug discovery, including the use of stem cells, antibody therapeutics, DNA-encoded libraries, and advances in COVID-19 therapeutics.
Goals and Objectives
The goal of the AGM workshop series is to help participants design and implement robust assays in early translation research by providing them a broad, practical perspective on assay development and data analysis. Our aim is to help participants improve their research projects involving drug discovery and know where to find further information; identify reagents, methods and instrumentation that are well suited to robust assays; and develop robust assays and the required counter and secondary assays for targets of interest. The workshops also provide participants with broad overviews and practical perspectives on new and emerging modalities in drug discovery.
View the agenda (PDF - 267KB)
Day 1: Nov. 18, 2020
Welcome to the AGM Workshop
Christopher P. Austin, M.D.
Director
National Center for Advancing Translational Sciences (NCATS)
In his welcome address, Dr. Austin introduces the audience to NCATS, its mission to conduct and disseminate translational science, and to the Assay Guidance Manual (AGM). Dr. Austin also highlights the upcoming events on the AGM calendar.
Robust or Go Bust: An Introduction to the Assay Guidance Manual
Sarine Markossian, Ph.D.
Editor-in-Chief, Assay Guidance Manual (AGM); Lead, AGM Translational Science Resources Program
National Center for Advancing Translational Sciences (NCATS)
Dr. Markossian introduces the audience to assays and their importance in the drug discovery pipeline, and to the Assay Guidance Manual (AGM) program including the e-book and the workshops. Dr. Markossian also highlights the objectives and goals of the workshop.
Target Qualification Strategies: Functional Genomics for Target ID and Validation
Yueming Wang Ph.D.
Principal Scientist, Primary Pharmacology Group, Medicine Design
Pfizer Inc.
Dr. Wang discusses the importance of improving the quality of target selection and details strategies to achieve that goal. He also takes a deep dive into the importance of functional genomics for target ID and validation.
Strategies for Assay Selection and for the Development of Robust Biochemical Assays
Nathan P. Coussens, Ph.D.
Director, Molecular Pharmacology Laboratories
Frederick National Laboratory for Cancer Research
Dr. Coussens discusses strategies for choosing the right assay for HTS. Dr. Coussens also expands on biochemical assays for enzymes and for molecular interactions.
Treating Cells as Reagents to Design Reproducible Assays
Terry Riss, Ph.D.
Senior Product Manager, Cell Health
Promega Corporation
Dr. Riss provides strategies to help design reproducible cell-based assays. He also addresses the major causes of variability in cell-based assays and provides avenues for establishing SOPs for consistent handling of cells.
High Content Imaging Applications: Best Practices and Approaches to Consider
Joe Trask
Product Line Leader & Senior Application Scientist, Cellular Imaging and Analysis
PerkinElmer
Mr. Trask introduces the audience to all of the current and upcoming AGM high-content screening (HCS) chapters. This talk also covers an overview of a typical HCS Workflow including its bottlenecks, 3D HCS imaging considerations and an introduction to cell painting.
Biophysical Approaches to Small Molecule Discovery and Validation
Michelle Arkin, Ph.D.
Professor, Pharmaceutical Chemistry; Co-Director, Small Molecule Discovery Center
University of California, San Francisco
Dr. Arkin describes the role of biophysical methods in drug discovery. Dr. Arkin first provides an overview of commonly used methodologies, and then describes fragment-based discovery as an application of biophysical methods in screening.
Compound-mediated Interferences in Homogeneous Proximity Assays
Jayme L. Dahlin, M.D., Ph.D., FASCP
Preclinical Medical Director, A Specialized Platform for Innovative Research Exploration (ASPIRE)
National Center for Advancing Translational Sciences (NCATS)
Dr. Dahlin provides a background on homogeneous proximity assays and discusses several compound interference mechanisms in these assays. Dr. Dahlin also provides strategies to identify and mitigate compound interferences.
In Vitro Toxicological Testing using a qHTS Platform
Menghang Xia, Ph.D.
Group leader, Systems Toxicology, Division of Preclinical Innovation
National Center for Advancing Translational Sciences (NCATS)
Dr. Xia introduces the audience to the Tox21 program and further discusses the selection and design of assays used in this program. She then presents a case study for a mitochondrial membrane potential assay as an example of an application of qHTS in toxicology.
Lead Selection and Optimization by Medicinal Chemistry
Samarjit Patnaik, Ph.D.
Group Leader, Chemistry, Early Translation Branch, Division of Preclinical Innovation
National Center for Advancing Translational Sciences (NCATS)
Dr. Patnaik emphasizes the importance of assay development to medicinal chemistry. He discusses multiple case studies where a change in the assay platform or conditions led to the discovery of unexpected activities of compounds.
In Vitro Assessment of ADME Properties of Lead Compounds
Xin Xu, Ph.D.
Senior scientist and the director of pharmacokinetics (PK), Therapeutics Development Branch, Division of Preclinical Innovation
National Center for Advancing Translational Sciences (NCATS)
Dr. Xu describes the importance of ADME/PK concepts in drug discovery and development. She also describes the development of in vitro assays to address key ADME issues, and introduces common ADME assays used in drug discovery and development.
Day 2: Nov. 19, 2020
Basic Assay Statistics, Data Analysis & Rules of Thumb (ROT)
Thomas “TC” D.Y. Chung, Ph.D.
Director, Translational Outreach Programs
Sanford Burnham Prebys Medical Discovery Institute
Dr. Chung introduces basic statistical concepts for proper HTS data analysis and validation. Dr. Chung then describes the Z-factor (Z’) as a simple parameter that summarizes an assay’s robustness.
Reproducibility Assessment of In Vitro Screening Results
Viswanath Devanarayan, Ph.D., FAAPS
Senior Statistics Director
GlaxoSmithKline
Dr. Devanarayan introduces minimum significant ratio (MSR) as a metric for evaluating the reproducibility of potency results from dose-response screening assays. He then discusses how MSR is calculated and describes different ways of estimating MSR.
Assay Operations: Keeping your Assays Robust and Reproducible
Jeffrey R. Weidner, Ph.D.
Founder
QualSci Consulting, LLC
Dr. Weidner introduces and defines key statistical concepts for assay robustness and reproducibility. He then introduces the audience to Statistical Process Control (SPC) which applies statistical methods to optimize reproducibility, reliability and quality.
Kinetics of Target Binding: Impact on Drug Activity from Bench to Bedside
Sam Hoare, Ph.D.
Founder
Pharmechanics, LLC
Dr. Hoare introduces basic concepts and principles in binding kinetics and its impact on drug measurements. Dr. Hoare then describes methodologies for measuring binding kinetics and highlights when to apply kinetics in drug discovery.
Why You Want to Use Stem Cells for Drug Discovery
Marcie Glicksman, Ph.D.
Head of Biology
EnClear Therapies
Dr. Glicksman emphasizes the importance of using stem cells in drug discovery campaigns and describes different stem cell technologies utilized in drug discovery. Dr. Glicksman also provides examples and case studies where stem cells were used in the drug discovery process as well as for therapy.
Toward the Efficient Discovery of Actionable Chemical Matter from DNA-encoded Libraries
Timothy L. Foley, Ph.D.
Pharmacology & DEL Selection Biology Lab Head, Primary Pharmacology Group
Pfizer Inc.
Dr. Foley introduces DNA-encoded chemical libraries (DEL) and describes how they are used for lead discovery. Dr. Foley then addresses several topics including reproducibility in DEL screens, hit selection and conformation, as well as some challenges in these processes.
Antibody Binding Sites as Therapeutics: From scFv to VHH and VNAR
Mitchell Ho, Ph.D.
Deputy Chief, Laboratory of Molecular Biology
National Cancer Institute (NCI), NIH
Dr. Ho describes different approaches for therapeutic antibody discovery. He then introduces the concept of antibody binding site as therapeutics and takes a deep dive into the utility of single-chain variable fragment (scFv) and single domain antibodies in therapeutics.
COVID19: The NCATS Experience
Matthew D. Hall, Ph.D.
Director, Early Translation Branch, Division of Preclinical Innovation
National Center for Advancing Translational Sciences (NCATS)
Dr. Hall describes activities conducted by NCATS to address COVID-19 including SARS-CoV-2 assay development and screening, as well as the launch of an open data portal to share COVID-19 drug repurposing data in real time.
Closing Remarks
Anton Simeonov, Ph.D.
Scientific Director, Division of Preclinical Innovation
National Center for Advancing Translational Sciences (NCATS)
In his closing remarks, Dr. Simeonov describes the AGM as a freely available resource for early discovery and emphasizes that the AGM program is becoming a community of followers, practitioners, and disseminators. Dr. Simeonov highlights the future directions and the upcoming events of the AGM.