Molecular basis of drug resistance in smoothened receptor: An in silico study of protein resistivity and specificity

N. Sinha, S. Chowdhury, R. Sarkar
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引用次数: 7

Abstract

Smoothened (SMO) antagonist Vismodegib effectively inhibits the Hedgehog pathway in proliferating cancer cells. In early stage of treatment, Vismodegib exhibited promising outcomes to regress the tumors cells, but ultimately relapsed due to the drug resistive mutations in SMO mostly occurring before (primary mutations G497W) or after (acquired mutations D473H/Y) anti‐SMO therapy. This study investigates the unprecedented insights of structural and functional mechanism hindering the binding of Vismodegib with sensitive and resistant mutant variants of SMO (SMOMut). Along with the basic dynamic understanding of Vismodegib‐SMO complexes, network propagation theory based on heat diffusion principles is first time applied here to identify the modules of residues influenced by the individual mutations. The allosteric modulation by GLY497 residue in Vismodegib bound SMO wild‐type (SMOWT) conformation depicts the interconnections of intermediate residues of SMO with the atom of Vismodegib and identify two important motifs (E‐X‐P‐L) and (Q‐A‐N‐V‐T‐I‐G) mediating this allosteric regulation. In this study a novel computational framework based on the heat diffusion principle is also developed, which identify significant residues of allosteric site causing drug resistivity in SMOMut. This framework could also be useful for assessing the potential allosteric sites of different other proteins. Moreover, previously reported novel inhibitor “ZINC12368305,” which is proven to make an energetically favorable complex with SMOWT is chosen as a control sample to assess the impact of receptor mutation on its binding and subsequently identify the important factors that govern binding disparity between Vismodegib and ZINC12368305 bound SMOWT/Mut conformations.
平滑受体耐药的分子基础:蛋白质电阻率和特异性的计算机研究
Smoothened (SMO)拮抗剂Vismodegib有效抑制癌细胞增殖中的Hedgehog途径。在治疗早期,Vismodegib显示出令人满意的肿瘤细胞退化效果,但由于SMO的耐药突变主要发生在抗SMO治疗之前(原发突变G497W)或之后(获得性突变D473H/Y),最终复发。本研究对阻碍Vismodegib与SMO敏感和耐药突变体(SMOMut)结合的结构和功能机制进行了前所未有的深入研究。随着对Vismodegib - SMO复合物的基本动态认识,本文首次应用基于热扩散原理的网络传播理论来识别受单个突变影响的残基模块。GLY497残基在Vismodegib结合的SMO野生型(SMOWT)构象中的变构调节描述了SMO中间残基与Vismodegib原子的相互联系,并鉴定了介导这种变构调节的两个重要基序(E‐X‐P‐L)和(Q‐A‐N‐V‐T‐I‐G)。本研究还提出了一种基于热扩散原理的计算框架,用于识别SMOMut中引起药物电阻率的变构位点的重要残余。该框架也可用于评估不同其他蛋白质的潜在变构位点。此外,选择先前报道的新型抑制剂“ZINC12368305”作为对照样本,以评估受体突变对其结合的影响,并随后确定控制Vismodegib与ZINC12368305结合的SMOWT/Mut构象之间结合差异的重要因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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