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

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 optimization and design of selective inhibitors that could suppress anti-apoptotic activities of Bcl2-family proteins with minimal toxicities.

Does Size Really Matter? Probing the Efficacy of Structural Reduction in the Optimization of Bioderived Compounds – A Computational “Proof-of-Concept”

“…Having investigated the differential pharmacokinetic and binding properties of Ang-D and SB640, it was also necessary to study their consequential implications on CRM1 secondary structure. This was important to determine the degree of alterations induced in the target protein upon binding since the conformational architecture of a protein are essential for its biological roles, while on the other hand, considerable alterations (due to ligand binding or mutational occurrences), could correlate with its inactivation [ 56 , 59 , 117 ]. In this study, we distinctively investigated the corresponding effects of Ang-D and SB640 on CRM1 structural architecture with regards to the blockage of nucleocytoplasmic trafficking.…”

“…The best docked complexes were identified based on the highest negative binding energies and obtained using UCSF chimera [ 55 ]. These pre-MD simulation protocols have been reported in our previous studies [ 56 , 57 ]. These systems, which include CRM1 in its unbound form and those separately bound by Ang-D and SB640 were subsequently setup for MD simulations using in-house protocols previously reported [ [57] , [58] , [59] ].…”

CF3‐Pyridinyl Substitution on Antimalarial Therapeutics: Probing Differential Ligand Binding and Dynamical Inhibitory Effects of a Novel Triazolopyrimidine‐Based Inhibitor on Plasmodium falciparum Dihydroorotate Dehydrogenase

“…Molecular dynamic (MD) simulations reveal essential insight into the dynamical evolution of biological systems by exploring the physical motions of atoms and molecules . The GPU version of the PMEMD engine incorporated in the AMBER 18 package was integrated to run the MD simulation on all systems.…”

Piece of the Puzzle: Remdesivir disassemble the multimeric SARS-CoV-2 RNA-dependent RNA Polymerase Non-Structural Proteins (RdRp-NSPs) complex

“…43 Relative stabilities of the SARS-CoV-2 multimers were determined by measuring the Cα-root mean square deviations (RMSDs) while other metrics such as the root mean square fluctuation (RMSF), radius of gyration (RoG) and solvent accessibility surface area (SASA) were used to measure perresidual motions, structural compactness, and solvent-surface motions. [30][31][32]35,44,45 Trajectorial motions of the molecules were also projected along two principal components (PC1 and PC2) for insights into their dynamics and motion patterns. [46][47][48] Data plots and snapshots for timebased visual analysis were obtained using the Origin analytical software and UCSF Chimera GUI 49 , Biovia Discovery Studio 50 and GIMP 2.0.…”