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Histone deacetylases have been recognized as a potential target for epigenetic aberrance reversal in the various strategies for cancer therapy, with HDAC6 implicated in various forms of tumor growth and cancers. Diverse inhibitors of HDAC6 has been developed, however, there is still the challenge of iso-specificity and toxicity. In this study, we trained a Random forest model on all HDAC6 inhibitors curated in the ChEMBL database (3,742). Upon rigorous validations the model had an 85% balanced accuracy and was used to screen the SCUBIDOO database; 7785 hit compounds resulted and were docked into HDAC6 CD2 active-site. The top two compounds having a benzimidazole moiety as its zinc-binding group had a binding affinity of -78.56kcal/mol and -78.21kcal/mol respectively. The compounds were subjected to exhaustive docking protocols (Qm-polarized docking and Induced-Fit docking) in other to elucidate a binding hypothesis and accurate binding affinity. Upon optimization, the compounds showed improved binding affinity (-81.42kcal/mol), putative specificity for HDAC6, and good ADMET properties. We have therefore developed a reliable model to screen for HDAC6 inhibitors and suggested a series of benzimidazole based inhibitors showing high binding affinity and putative specificity for HDAC6.

Evading apoptosis is one of the hallmarks of cancer cells, therefore a lot of therapeutic strategies have been developed to induce cell death in these cells. BCL2 family protein governs the intrinsic pathway of cell death. The BCL2 family protein possess both pro and anti-apoptosis members. BCL2 protein, a pioneering member of the anti-apoptosis protein has been implicated in several cancerous cells; with dozens of small-molecule inhibitors developed to inhibit its activity. BCL2 family protein processes BH domains (1-4) for heterodimerization and homodimerization amidst it family members and targeting the BH4 domain is an established new strategy for cancer therapy; however, only BDA366 has been reported so far as a BH4 binding molecule. Using Computer-aided drug discovery techniques (Molecular docking, QM-polarized docking, Induced-fit docking, QM-MM optimization, and QM electronic descriptors) we screened M sample (∼ 99,000 compounds) of the SCUBIDOO database to find ligands that interacts with the BH4 domain of BCL2 protein with high affinity, we identified 11 putative BH4 specific small molecules with binding affinity ranging from ∼ −84kcal/mol to −64kcal/mol with a putative binding hypothesis with BH4 amino acid residues: ASP10, ARG12, GLU13, MET16, LYS17, and HIS20