Virtual Screening and Elucidation of Putative Binding Mode for Small Molecule Antagonist of BCL2 BH4 Domain

Abstract

Evading apoptosis is a hallmark of cancer cells, therefore therapeutic strategies have been developed to induce cell death. BCL2 family protein governs the intrinsic pathway of cell death. Targeting the BH4 domain to modulate the anti-apoptosis activities of BCL2 protein has been established however, BDA366 is the only BH4 binding molecule to be reported. Virtually screening ~ 1,000,000 compounds 11 putative BH4 binding small molecules with binding affinity ~ -84kcal/mol to - 64kcal/mol resulted. Using QM-polarized docking, Induced-fit docking, and QM-MM optimization, a putative binding mode for the top 3 compounds is proposed: compound 139068 interactions with GLU13, MET16, LYS17, ASP31, and GLU42; compound 138967 interactions with ASP10, ARG12, GLU13, HIS20, MET16, and GLU42; compound 38831 interactions with ASP10, ARG12, GLU13, LYS17, and GLU42. MD simulations (NMA) data showed the binding of the three compounds to be stable with low eigenvalues. Electronic properties derived via DFT calculations suggest chemical reaction of the compounds be via electrophilic reactions.