Virtual screening identification of novel severe acute respiratory syndrome 3C-like protease inhibitors and in vitro confirmation

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• 作者：Thi Thanh Hanh Nguyen^a ; Hwa-Ja Ryu^b ; Se-Hoon Lee^c ; Soonwook Hwang^c ; Vincent Breton^d ; Joon Haeng Rhee^e ; Doman Kim^a ; ^{dmkim@jnu.ac.kr"" rel=""nofollow}
• 关键词：3CL Protease ; Severe acute respiratory syndrome ; SARS ; Coronavirus ; FRET-based assays ; Autodock ; Virtual screening ; Grid
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：15 May 2011
• 年：2011
• 卷：21
• 期：10
• 页码：3088-3091
• 全文大小：524 K

文摘

The 3C-like protease (3CL^pro) of severe acute respiratory syndrome associated coronavirus (SARS-CoV) is vital for SARS-CoV replication and is a promising drug target. Structure based virtual screening of 308 307 chemical compounds was performed using the computation tool Autodock 3.0.5 on a WISDOM Production Environment. The top 1468 ranked compounds with free binding energy ranging from −14.0 to −17.09 kcal mol⁻¹ were selected to check the hydrogen bond interaction with amino acid residues in the active site of 3CL^pro. Fifty-three compounds from 35 main groups were tested in an in vitro assay for inhibition of 3CL^pro expressed by Escherichia coli. Seven of the 53 compounds were selected; their IC₅₀ ranged from 38.57 ± 2.41 to 101.38 ± 3.27 μM. Two strong 3CL^pro inhibitors were further identified as competitive inhibitors of 3CL^pro with K_i values of 9.11 ± 1.6 and 9.93 ± 0.44 μM. Hydrophobic and hydrogen bond interactions of compound with amino acid residues in the active site of 3CL^pro were also identified.