利用分子对接、分子动力学模拟和结合自由能计算评估丙型肝炎病毒NS3/4A与磺胺基苯甲酰胺分子之间的相互作用

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jinhong Ren, Tasneem M. Vaid, Hyun Lee, Isabel Ojeda, Michael E. Johnson
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引用次数: 2

摘要

丙型肝炎病毒(HCV) NS3/4A是治疗丙型肝炎感染的一个有吸引力的靶点。在此,我们提出了一项基于磺胺苯甲酰胺支架的HCV NS3/4A抑制剂的研究。通过分子对接、分子动力学模拟和MM/PBSA结合自由能计算,探讨抑制剂与HCV NS3/4A的相互作用。所有抑制剂在蛋白酶的催化位点都采用相似的分子对接姿势,通过与G137和催化剂S139的氢键相互作用来稳定蛋白酶的分子对接姿势,这对于效力和结合稳定性至关重要。MM/PBSA对结合自由能的定量评价与实验结果吻合良好,具有较高的决定系数,R2为0.92。结合自由能分解分析阐明了Q41、F43、H57、R109、K136、G137、S138、S139、A156、M485和Q526在结合不同抑制剂方面的不同贡献。计算丙氨酸扫描诱变进一步证实了这些侧链的重要性。此外,K136和S139的侧链对抑制剂与HCV NS3/4A的结合表现出重要但不同的作用。该效价的结构基础已被阐明,证明了R155侧链构象的重要性。在原子水平上对这些化合物与HCV NS3/4A之间的结合能和相互作用的广泛探索将有助于未来的抗病毒药物设计。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Evaluation of interactions between the hepatitis C virus NS3/4A and sulfonamidobenzamide based molecules using molecular docking, molecular dynamics simulations and binding free energy calculations

Evaluation of interactions between the hepatitis C virus NS3/4A and sulfonamidobenzamide based molecules using molecular docking, molecular dynamics simulations and binding free energy calculations

The Hepatitis C Virus (HCV) NS3/4A is an attractive target for the treatment of Hepatitis C infection. Herein, we present an investigation of HCV NS3/4A inhibitors based on a sulfonamidobenzamide scaffold. Inhibitor interactions with HCV NS3/4A were explored by molecular docking, molecular dynamics simulations, and MM/PBSA binding free energy calculations. All of the inhibitors adopt similar molecular docking poses in the catalytic site of the protease that are stabilized by hydrogen bond interactions with G137 and the catalytic S139, which are known to be important for potency and binding stability. The quantitative assessments of binding free energies from MM/PBSA correlate well with the experimental results, with a high coefficient of determination, R2 of 0.92. Binding free energy decomposition analyses elucidate the different contributions of Q41, F43, H57, R109, K136, G137, S138, S139, A156, M485, and Q526 in binding different inhibitors. The importance of these sidechain contributions was further confirmed by computational alanine scanning mutagenesis. In addition, the sidechains of K136 and S139 show crucial but distinct contributions to inhibitor binding with HCV NS3/4A. The structural basis of the potency has been elucidated, demonstrating the importance of the R155 sidechain conformation. This extensive exploration of binding energies and interactions between these compounds and HCV NS3/4A at the atomic level should benefit future antiviral drug design.

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来源期刊
Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design 生物-计算机:跨学科应用
CiteScore
8.00
自引率
8.60%
发文量
56
审稿时长
3 months
期刊介绍: The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.
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