Mitigation and identification of aggregation and nonspecific reactivity interference in high-throughput screening
Recorded On: 06/07/2018
Compound-mediated assay interference and bioassay promiscuity are significant burdens in drug and chemical probe discovery. Pursuing artifacts or poorly tractable, nonselective chemical matter from real and virtual high-throughput screening (HTS) can waste significant scientific resources and can lead to tenuous scientific conclusions when used in subsequent studies. Two of the more prominent sources of generalized assay interference in biological assays by test compounds are aggregation and nonspecific reactivity. Aggregators and reactive compounds can interfere across multiple assay technologies and formats including biochemical and cellular systems, often leading to poorly tractable, promiscuous bioactivity. Apparent bioactivity from such interference compounds can be highly deceptive and quite convincing, even to experienced scientists. These subversive sources of apparent bioactivity represent significant project risks that can fortunately be mitigated with appropriate experimental design. This webinar will first discuss the fundamental chemical principles of these interferences, then introduce (1) technical recommendations to mitigate the incidence of aggregation and nonspecific reactivity in biological assays, and (2) basic and advanced counter-screens to identify as well as de-risk apparent bioactive compounds for aggregation and nonspecific reactivity. This information should be helpful for those performing HTS and triage, drug and chemical probe development, and chemical biology.
Jayme L. Dahlin, M.D., Ph.D.
Department of Pathology, Brigham and Women’s Hospital
Dr. Dahlin joined the Mayo Clinic (Rochester, MN) Medical Scientist Training Program in 2007 after earning his B.A. in chemistry from Carleton College (Northfield, MN). In 2016, he graduated with an M.D. from Mayo Medical School and a Ph.D. in Molecular Pharmacology and Experimental Therapeutics from Mayo Graduate School. He is currently Chief Resident in Clinical Pathology at Brigham and Women’s Hospital (Boston, MA) and a postdoctoral research fellow in the laboratory of Dr. Stuart L. Schreiber at the Broad Institute of Harvard/Massachusetts Institute of Technology. His graduate and postdoctoral work have focused on chemical mechanisms of biological assay interference and post-HTS triage. His research interests include HTS and triage tool development, bioassay promiscuity, and compound-mediated assay interference. Dr. Dahlin serves on the editorial board for the NIH Assay Guidance Manual and the Scientific Advisory Board of the Chemical Probes Portal.