The PubChem's BioAssay Database currently contains bioactivity screens from 1644 HTS programs with descriptions of each bioassay, covering thousands of targets, and providing millions of bioactivity outcomes. However, utilizing these resources towards identifying lead compounds for further development is still challenging. Through the NIH MLSCN Program, we have optimized ultra-HTS time-resolved fluorescence resonance energy transfer based assay to discover small-molecule inhibitors which block the interaction of Mcl-1 with either of two binding partners, Noxa and Bid. This assay was used to screen 102,255 compounds and 1384 hits were identified after secondary dose dependent screening. In order to identify the most promising hits, we integrated a computational structure-based searching strategy by applying induced-fit docking. Compounds for further evaluation were selected after analyzing the obtained docking poses and identifying which compounds mimic at least two conserved interactions that BH3 peptides have with the Mcl-1 protein. 56 compounds were purchased and characterized by using several different biochemical (fluorescence polarization and surface plasmon resonance based binding assays) and biophysical methods (N15 HSQC NMR spectroscopy) for their binding to the Mcl-1 protein and their selectivity against the other four members of the Bcl-2 family. Among the most potent identified compounds, 9 new chemical scaffolds were confirmed as binders to Mcl-1 with different selectivity profiles against five members of the Bcl-2 family. These results indicate that integrating the structure-based searching strategy for analyzing the published results in the PubChem's BioAssay Database represents useful tools towards identifying the most promising leads for the purpose of drug discovery.

Utilization of PubChem's BioAssay Database for drug discovery: Identification of Mcl-1 inhibitors with novel chemical scaffolds

244th National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.