Scientists at NCATS who specialize in chemistry technology have key expertise in synthetic and medicinal chemistry, assay design, and screening implementation. These experts pursue and develop additional areas of focus, including new bioinformatics techniques, “omics” integration strategies and novel strategies to probe pharmacology-to-phenotype assessments.
A snapshot of core and novel competencies follows:
- Synthetic and medicinal chemistry: These areas of chemistry are a key research focus for the program.
- Advancement of candidate small molecules and drug repositioning: This area involves development of bioactive small molecules through the pre-clinical pipeline, including performing pharmacokinetic/pharmacodynamics assessments; CMC (chemistry, manufacturing and control)–related activities, such as salt and crystal form determination; toxicity assessment of candidate agents; and repositioning of approved and investigational drugs.
- Library design and implementation: NCATS staff contribute to the design and implementation of mechanism interrogation plate (MIPe) libraries of pharmacologically defined small molecules with relevance to cancer, neurology, infectious diseases and stem cell biology.
- Phenotypic and matrix screening: Chemistry technology experts routinely develop and conduct phenotypic screens on MIPe libraries to determine mechanism-based relationships between phenotype and pharmacology. The matrix combination screening platform allows assessment of mechanistically related combination outcomes for basic and translational studies.
- “Omics”/phenotype/pharmacology relationships: Specified outcomes from phenotypic and matrix screening are analyzed based on the “omics” background (RNAseq, phosphoproteome and metabolome) to gain contextual understanding of the phenotypic outcomes from key pharmacologies.
- Deconstructed polypharmacologies: NCATS experts conduct analysis of the polypharmacology of specified agents to define the key target elements that give rise to a phenotypic outcome. These studies involve several techniques, including RNAi sensitization and in situ profiling technologies. Staff also redesign agents (often approved or investigational drugs) to home in on the polypharmacology and achieve an alternate profile.