Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
Chem Biodivers. 2022 Jul;19(7):e202100845. doi: 10.1002/cbdv.202100845. Epub 2022 Jun 8.
In recent times, the development of combination therapy has been a focal point in drug discovery. This article explores the potential synergistic effect of co-administration of Bcl2 inhibitor Venetoclax and BET inhibitor JQ1. We envisioned that the 'dual-site'-binding of Bcl2 has significant prospects and paves the way for the next round of rational design of potent Waldenström macroglobulinemia (WM) therapy. The preferential binding mechanisms of the multi-catalytic sites of the Bcl2 enzyme have been a subject of debate in the literature. This study conducted a systematic procedure to explore the preferred binding modes and the structural effects of co-binding at each catalytic active site. Interestingly, a mutual enhanced binding effect was observed - Venetoclax increased the binding affinity of JQ1 by 11.5 %, while JQ1 boosted the binding affinity of Venetoclax by 16.3 % when compared with individual inhibition of each drug. This synergistic binding effect has significantly increased protein stability, with substantial correlated movements and multiple van der Waals interactions. The structural and thermodynamic insights unveiled in this report would assist the future design of improved combined therapy against WM.
近年来，联合治疗的发展一直是药物发现的重点。本文探讨了 Bcl2 抑制剂 Venetoclax 和 BET 抑制剂 JQ1 联合给药的潜在协同效应。我们设想 Bcl2 的“双位点”结合具有重要的前景，并为下一代合理设计有效的 Waldenström 巨球蛋白血症 (WM) 治疗铺平了道路。Bcl2 酶的多催化位点的优先结合机制一直是文献中的一个争论点。本研究进行了系统的程序来探索每个催化活性位点的优先结合模式和结构效应。有趣的是，观察到了相互增强的结合效应——与单独抑制每种药物相比，Venetoclax 将 JQ1 的结合亲和力提高了 11.5%，而 JQ1 将 Venetoclax 的结合亲和力提高了 16.3%。这种协同结合效应显著增加了蛋白质稳定性，产生了大量相关运动和多个范德华相互作用。本报告中揭示的结构和热力学见解将有助于未来设计针对 WM 的改进联合治疗。
