Forging New Scaffolds from Old: Combining Scaffold Hopping and Hierarchical Virtual Screening for Identifying Novel Bcl-2 Inhibitors
Objective: In the current work, we made a novel attempt in terms of blending scaffold hopping and hierarchical virtual screening. The prime objective is to assess the hybrid method for its efficacy in identifying active lead molecules for emerging PPI target Bcl-2 (B-cell Lymphoma 2).
Methods: We designed novel scaffolds from the reported cores and screened a set of 8270 compounds using both scaffold hopping and hierarchical virtual screening for Bcl-2 protein. Also, we enumerated the libraries using clustering, PAINS filtering, physicochemical characterization and SAR matching.
Results: We generated a focused library of compounds towards Bcl-2 interface, screened the 8270 compounds and identified top hits for seven families upon fine filtering with PAINS algorithm, features, SAR mapping, synthetic accessibility and similarity search. Our approach retrieved a set of 50 lead compounds.
Conclusion: Finding rational approach meeting the needs of drug discovery process for PPI targets is the need of the hour which can be fulfilled by an extended scaffold hopping approach resulting in focused PPI targeting by providing novel leads with better potency.
Document Type: Research Article
Publication date: May 1, 2019
This article was made available online on July 9, 2019 as a Fast Track article with title: "Forging New Scaffolds from Old: Combining Scaffold Hopping and Hierarchical Virtual Screening for Identifying Novel Bcl-2 Inhibitors".