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.

中文翻译：

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平滑受体中药物抗性的分子基础：对蛋白质抗性和特异性的计算机模拟研究。

平滑化（SMO）拮抗剂Vismodegib有效抑制增殖癌细胞中的Hedgehog途径。在治疗的早期阶段，Vismodegib表现出使肿瘤细胞消退的有希望的结果，但由于SMO中的药物耐药性突变主要在抗SMO治疗（原发突变G497W）或之后（获得性突变D473H / Y）发生，最终得以复发。这项研究调查了阻碍Vismodegib与SMO（SMOMut）的敏感和耐药突变体结合的结构和功能机制的空前见解。除了对Vismodegib-SMO复合物的基本动态了解之外，在此首次应用基于热扩散原理的网络传播理论来确定受各个突变影响的残基模块。Vismodegib结合的SMO野生型（SMOWT）构象中GLY497残基的变构调节作用描绘了SMO中间残基与Vismodegib原子的相互连接，并确定了两个重要的基序（EXPL）和（QANVTIG）介导这种变构调节。在这项研究中，还开发了一种基于热扩散原理的新型计算框架，该框架确定了导致SMOMut中药物耐药性的变构位点的大量残基。该框架还可用于评估不同其他蛋白质的潜在变构位点。此外，先前报道的新型抑制剂“ ZINC12368305”