Background: Though virtual screening methods have proven to be potent in various instances, the
technique is practically incomplete to quench the need of drug discovery process. Thus, the quest for novel
designing approaches and chemotypes for improved efficacy of lead compounds has been intensified and logistic
approaches such as scaffold hopping and hierarchical virtual screening methods were evolved. Till now,
in all the previous attempts these two approaches were applied separately.
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.