Structure-Based Drug Design and Structural Biology Study of Novel Nonpeptide Inhibitors of Severe Acute Respiratory Syndrome Coronavirus Main Protease
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- 作者：I-Lin Lu ; Neeraj Mahindroo ; Po-Huang Liang ; Yi-Hui Peng ; Chih-Jung Kuo ; Keng-Chang Tsai ; Hsing-Pang Hsieh ; Yu-Sheng Chao ; Su-Ying Wu
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：August 24, 2006
- 年：2006
- 卷：49
- 期：17
- 页码：5154 - 5161
- 全文大小：388K
- 年卷期：v.49,no.17(August 24, 2006)
- ISSN：1520-4804
文摘
Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (Mpro), a protein required forthe maturation of SARS-CoV, is vital for its life cycle, making it an attractive target for structure-baseddrug design of anti-SARS drugs. The structure-based virtual screening of a chemical database containing58 855 compounds followed by the testing of potential compounds for SARS-CoV Mpro inhibition leads totwo hit compounds. The core structures of these two hits, defined by the docking study, are used for furtheranalogue search. Twenty-one analogues derived from these two hits exhibited IC50 values below 50 
M,with the most potent one showing 0.3 M. Furthermore, the complex structures of two potent inhibitorswith SARS-CoV Mpro were solved by X-ray crystallography. They bind to the protein in a distinct mannercompared to all published SARS-CoV Mpro complex structures. They inhibit SARS-CoV Mpro activity viaintensive H-bond network and hydrophobic interactions, without the formation of a covalent bond.Interestingly, the most potent inhibitor induces protein conformational changes, and the inhibition mechanisms,particularly the disruption of catalytic dyad (His41 and Cys145), are elaborated.
M,with the most potent one showing 0.3 M. Furthermore, the complex structures of two potent inhibitorswith SARS-CoV Mpro were solved by X-ray crystallography. They bind to the protein in a distinct mannercompared to all published SARS-CoV Mpro complex structures. They inhibit SARS-CoV Mpro activity viaintensive H-bond network and hydrophobic interactions, without the formation of a covalent bond.Interestingly, the most potent inhibitor induces protein conformational changes, and the inhibition mechanisms,particularly the disruption of catalytic dyad (His41 and Cys145), are elaborated.