• Acta Pharmacol. Sin. · Jun 2003

    A 3D model of SARS_CoV 3CL proteinase and its inhibitors design by virtual screening.

    • Bin Xiong, Chun-Shan Gui, Xiao-Ying Xu, Cheng Luo, Jing Chen, Hai-Bin Luo, Li-Li Chen, Guo-Wei Li, Tao Sun, Chang-Ying Yu, Li-Duo Yue, Wen-Hu Duan, Jing-Kang Shen, Lei Qin, Tie-Liu Shi, Yi-Xue Li, Kai-Xian Chen, Xiao-Min Luo, Xu Shen, Jian-Hua Shen, and Hua-Liang Jiang.
    • Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
    • Acta Pharmacol. Sin. 2003 Jun 1; 24 (6): 497-504.

    AimTo constructed a three-dimensional (3D) model for the 3C like (3CL) proteinase of SARS coronavirus (SARS-CoV), and to design inhibitors of the 3CL proteinase based on the 3D model.MethodsBioinformatics analyses were performed to search the homologous proteins of the SARS-CoV 3CL proteinase from the GenBank and PDB database. A 3D model of the proteinase was constructed by using homology modeling technique. Targeting to the 3D model and its X-ray crystal structure of the main proteinase (Mpro) of transmissible gastroenteritis virus (TGEV), virtual screening was performed employing molecular docking method to identify possible 3CL proteinase inhibitors from small molecular databases.ResultsSequence alignment indicated that the SARS-CoV 3CL proteinase was extremely homologous to TGEV Mpro, especially the substrate-binding pocket (active site). Accordingly, a 3D model for the SARS-CoV 3CL proteinase was constructed based on the crystal structure of TGEV Mpro. The 3D model adopts a similar fold of the TGEV Mpro, its structure and binding pocket feature are almost as same as that of TGEV Mpro. The tested virtual screening indicated that 73 available proteinase inhibitors in the MDDR database might dock into both the binding pockets of the TGEV Mpro and the SARS-CoV 3CL proteinase.ConclusionsEither the 3D model of the SARS-CoV 3CL proteinase or the X-ray crystal structure of the TGEV Mpro may be used as a starting point for design anti-SARS drugs. Screening the known proteinase inhibitors may be an appreciated shortcut to discover anti-SARS drugs.

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