Molecular recognition mechanism and motion of HCV NS3/4A protease with Faldaprevir analogue.

Li Liang; Jianping HU; Wenyi DU; Ke Zuo; Wei Liu; Xiaojun Gou

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Molecular recognition mechanism and motion of HCV NS3/4A protease with Faldaprevir analogue.

Author: Li LIANG ¹ ; Jianping HU ¹ ; Wenyi DU ¹ ; Ke ZUO ¹ ; Wei LIU ¹ ; Xiaojun GOU ¹
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1. Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610106, Sichuan, China.
Publication Type:Journal Article
Keywords: Faldaprevir analogue molecule; HCV NS3/4A protease; binding free energy; conformational change; molecular dynamics simulation
MeSH: Antiviral Agents; chemistry; Carrier Proteins; chemistry; Drug Resistance, Viral; Endopeptidases; Hepacivirus; Molecular Dynamics Simulation; Mutagenesis, Site-Directed; Oligopeptides; chemistry; Protease Inhibitors; chemistry; Serine Proteases; Thiazoles; chemistry; Viral Nonstructural Proteins; chemistry
From: Chinese Journal of Biotechnology 2016;32(5):669-682
CountryChina
Language:Chinese
Abstract: Faldaprevir analogue molecule (FAM) has been reported to effectively inhibit the catalytic activity of HCV NS3/4A protease, making it a potential lead compound against HCV. A series of HCV NS3/4A protease crystal structures were analyzed by bioinformatics methods, and the FAM-HCV NS3/4A protease crystal structure was chosen for this study. A 20.4 ns molecular dynamics simulation of the complex consists of HCV NS3/4A protease and FAM was conducted. The key amino acid residues for interaction and the binding driving force for the molecular recognition between the protease and FAM were identified from the hydrogen bonds and binding free energy analyses. With the driving force of hydrogen bonds and van der Waals, FAM specifically bind to the active pocket of HCV NS3/4A protease, including V130-S137, F152-D166, D77-D79 and V55, which agreed with the experimental data. The effect of R155K, D168E/V and V170T site-directed mutagenesis on FAM molecular recognition was analyzed for their effect on drug resistance, which provided the possible molecular explanation of FAM resistance. Finally, the system conformational change was explored by using free energy landscape and conformational cluster. The result showed four kinds of dominant conformation, which provides theoretical basis for subsequent design of Faldaprevir analogue inhibitors based on the structure of HCV NS3/4A protease.