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, 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. Natural gossypol is toxic, less soluble in water, and anti-fertility agent, therefore, 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. Molecular interactions involving H-bonds between protein and ligands were deduced based on dock score functions. 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. Although drug likeliness is not significant for the top ranked molecules, but they are good leads for the further improvement and synthesis of functionally valid BH3 mimetics.

DOI: 10.4172/2169-0138.1000155

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Editor Board
Drug Designing: Open Access
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