Probing Gallate-Mediated Selectivity and High-Affinity Binding of Epigallocatechin Gallate: a Way-Forward in the Design of Selective Inhibitors for Anti-apoptotic Bcl-2 Proteins

Applied Biochemistry and Biotechnology
Fisayo A OlotuMahmoud E Soliman

Abstract

Selective inhibition is a key focus in the design of chemotherapeutic compounds that can abrogate the oncogenic activities of anti-apoptotic Bcl-2 proteins. Although recent efforts have led to the development of highly selective BH3 mimetics, setbacks such as toxicities have limited their use in cancer therapy. Epigallocatechingallate (EGCG) has been widely reported to selectively inhibit Bcl-2 and Bcl-xL compared to other green tea phenols due to its gallate group. Herein, we investigate the interaction dynamics of EGCG at the hydrophobic grooves of Bcl-2 and Bcl-xL and the consequential effects on their BH4 domains. Arg143 and Asp108 (Bcl-2), and Glu96 and Tyr195 (Bcl-xL) formed high-affinity hydrogen interactions with the gallate group while non-gallate groups of EGCG formed weak interactions. EGCG-bound proteins showed systemic perturbations of BH4 domains coupled with the burial of crucial surface-exposed residues such as Lys17 (Bcl-2) and Asp11 (Bcl-xL); hence, a distortion of non-canonical domain interactions. Interactions of gallate group of EGCG with key hydrophobic groove residues underlie EGCG selectivity while concurrent BH4 domain perturbations potentiate EGCG inhibitory activities. Findings will aid the optimizati...Continue Reading

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Citations

Apr 6, 2019·Anti-cancer Agents in Medicinal Chemistry·Aimen K AljoundiMahmoud E S Soliman
Oct 27, 2020·Journal of Biomolecular Structure & Dynamics·Joyce Oloaigbe OgidigoMahmoud E S Soliman
Jan 26, 2020·Computational Biology and Chemistry·Elliasu Y SalifuMahmoud E S Soliman
Aug 26, 2020·South African Journal of Botany : Official Journal of the South African Association of Botanists = Suid-Afrikaanse Tydskrif Vir Plantkunde : Amptelike Tydskrif Van Die Suid-Afrikaanse Genootskap Van Plantkundiges·Depika DwarkaHimansu Baijnath
Apr 2, 2021·Cell Biochemistry and Biophysics·Fisayo A OlotuMahmoud E S Soliman

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