title: A high-throughput screen for aggregation-based inhibition in a large compound library.
abstract: High-throughput screening (HTS) is the primary technique for new lead identification in drug discovery and chemical biology. Unfortunately, it is susceptible to false-positive hits. One common mechanism for such false-positives is the congregation of organic molecules into colloidal aggregates, which nonspecifically inhibit enzymes. To both evaluate the feasibility of large-scale identification of aggregate-based inhibition and quantify its prevalence among screening hits, we tested 70,563 molecules from the National Institutes of Health Chemical Genomics Center (NCGC) library for detergent-sensitive inhibition. Each molecule was screened in at least seven concentrations, such that dose-response curves were obtained for all molecules in the library. There were 1274 inhibitors identified in total, of which 1204 were unambiguously detergent-sensitive. We identified these as aggregate-based inhibitors. Thirty-one library molecules were independently purchased and retested in secondary low-throughput experiments; 29 of these were confirmed as either aggregators or nonaggregators, as appropriate. Finally, with the dose-response information collected for every compound, we could examine the correlation between aggregate-based inhibition and steep dose-response curves. Three key results emerge from this study: first, detergent-dependent identification of aggregate-based inhibition is feasible on the large scale. Second, 95% of the actives obtained in this screen are aggregate-based inhibitors. Third, aggregate-based inhibition is correlated with steep dose-response curves, although not absolutely. The results of this screen are being released publicly via the PubChem database.
authors: Department of Pharmaceutical Chemistry & Graduate Group in Chemistry and Chemical Biology, 1700 4th Street, University of California San Francisco, San Francisco, California 94158-2330, USA.
authors: Brian Y
authors: BY
authors: Feng
authors: Anton
authors: A
authors: Simeonov
authors: Ajit
authors: A
authors: Jadhav
authors: Kerim
authors: K
authors: Babaoglu
authors: James
authors: J
authors: Inglese
authors: Brian K
authors: BK
authors: Shoichet
authors: Christopher P
authors: CP
authors: Austin
mesh_terms: D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003102:Colloids; D003902:Detergents / Q000737:chemistry*; D015195:Drug Design; D005240:Feasibility Studies; D007700:Kinetics; D009930:Organic Chemicals / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D001618:beta-Lactamases / Q000737:chemistry
chemical_list: D003102:Colloids; D003902:Detergents; D009930:Organic Chemicals; D004364:Pharmaceutical Preparations; D001618:beta-Lactamases