Molecular Docking Studies of Hydrazide-Hydrazone Derivatives of Gossypol against Bcl-2 Family Anti-Apoptotic Targets

Abstract

Background: In tumor progression, BH3 domain containing Bcl-2 family members, anti-apoptotic proteins, are potential targets for cancer therapy. BH3 domain inhibitors or BH3 mimetics, a novel class of anti-cancer drugs, promote the apoptosis by inhibiting Bcl-2 family proteins that are highly conserved mitochondrial intrinsic apoptotic pathway members. Methods: In the present study, we have designed 54 different gossypol derivatives and evaluated their potency by molecular docking studies. Molecular interaction between popular BH3 domain containing targets Bcl-2, Bcl-w, Bcl-xL and Mcl-1 and gossypol derivatives were investigated by dock score function. Results: 54 chemo sensitive hydrazide-hydrazone gossypol derivatives (3a-3r) were designed to evaluate their binding interaction stability with the antiapoptotic targets Bcl-2, Bcl-w, Bcl-xL, and Mcl-1. Among interactions, Bcl-2 and gossypol derivative 3k has shown better interaction. Finally, pharmacokinetic property of each lead molecule against specific target was further probed to assess the drug likeliness. Conclusion: Bcl-2 and gossypol derivative 3k complex has shown better interaction among Bcl-2 family members. Top ranked hydrazide-hydrazone gossypol derivatives against each anti-apoptotic target were further probed for ADME properties.