Molecular Modelling Analysis of Squamocin as Potential BCL-XL Anti-apoptotic Protein Inhibitor

Kaynat Khimani¹, Mohd Faiz Abdul Ghani^1,2, Rozana Othman³, Noraziah Nordin^1,*

Abstract

Introduction: BCL-XL is one of the prosurvival proteins that is overexpressed in certain cancers and implicated as a chemoresistance factor. It is known from in-vitro studies that certain acetogenins, including squamocin (SQ), have potent anticancer properties. However, its inhibitory effect towards BCL-XL has not been established. In this study, we evaluated the interaction and binding affinity of SQ into BCL-XL protein in molecular docking and dynamics. Methods: Autodock Vina was used to perform molecular docking of SQ with BCL-XL protein. The tested ligand was also compared with ABT-737, a known BCL-XL inhibitor. The best conformation with lowest binding energy and interaction with key active residues of BCL-XL receptor was chosen. The complex was further subjected to a molecular dynamic study for 100ns simulation using FF19SB forcefield in Amber 22. Molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) energy calculations, Root mean square deviation (RMSD) and Fluctuation of protein conformation (RMSF) of the complex were performed. Results: Interaction of SQ with the active site of BCL-XL protein revealed a better binding affinity of -11.9 kcalmol-1 compared to -9.179 kcalmol-1 of ABT-737. The SQ/BCLXL complex was found to be stable throughout 100ns simulation time. Furthermore, hydrogen bonding patterns between key residues of ARG139 and SER 109 with SQ ligand were detected, and energy profiles reflect the stability of the bound complex. Conclusion: Squamocin is a potential inhibitor of the BCL-XL protein based on the in-silico study. However, a further experimental study is needed to validate its action toward the development of a new drug for cancer therapy. 

Keywords: Cancer, Squamocin, BCL-XL protein, Molecular docking, Molecular dynamic

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