[논문]Binding interaction of quercetin-3-β-galactoside and its synthetic derivatives with SARS-CoV 3CLpro: Structure–activity relationship studies reveal salient pharmacophore features

doi:10.1016/j.bmc.2006.09.014

Binding interaction of quercetin-3-β-galactoside and its synthetic derivatives with SARS-CoV 3CLpro: Structure–activity relationship studies reveal salient pharmacophore features 원문보기

Bioorganic & medicinal chemistry, v.14 no.24, 2006년, pp.8295 - 8306

Chen, Lili (Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China) , Li, Jian (Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China) , Luo, Cheng (Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China) , Liu, Hong (Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China) , Xu, Weijun (Technology Centre for Life Sciences, Singapore Polytechnic, 500 Dover Road, 139651 Singapore, Singapore) , Chen, Gang (Technology Centre for Life Sciences, Singapore Polytechnic, 500 Dover Road, 139651 Singapore, Singapore) , Liew, Oi Wah (Technology Centre for Life Sciences, Singapore Polytechnic, 500 Dover Road, 139651 Singapore, Singapore) , Zhu, Weiliang (Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China) , Puah, Chum Mok (Technology Centre for Life Sciences, Singapore Polyt) , Shen, Xu , Jiang, Hualiang

Abstract ▼ AI-Helper

Graphical abstractA new class of compounds that have been designed and synthesized based on a natural product, quercetin-3-β-galactoside, has been discovered to be effective inhibitors of SARS coronavirus 3CL protease (SARS-CoV 3CLpro), which could be developed as drug leads for SARS. AbstractThe 3C-like protease (3CLpro) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for discovery of drugs against SARS, because of its critical role in the viral life cycle. In this study, a natural compound called quercetin-3-β-galactoside was identified as an inhibitor of the protease by molecular docking, SPR/FRET-based bioassays, and mutagenesis studies. Both molecular modeling and Q189A mutation revealed that Gln189 plays a key role in the binding. Furthermore, experimental evidence showed that the secondary structure and enzymatic activity of SARS-CoV 3CLpro were not affected by the Q189A mutation. With the help of molecular modeling, eight new derivatives of the natural product were designed and synthesized. Bioassay results reveal salient features of the structure–activity relationship of the new compounds: (1) removal of the 7-hydroxy group of the quercetin moiety decreases the bioactivity of the derivatives; (2) acetoxylation of the sugar moiety abolishes inhibitor action; (3) introduction of a large sugar substituent on 7-hydroxy of quercetin can be tolerated; (4) replacement of the galactose moiety with other sugars does not affect inhibitor potency. This study not only reveals a new class of compounds as potential drug leads against the SARS virus, but also provides a solid understanding of the mechanism of inhibition against the target enzyme.

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Binding interaction of quercetin-3-β-galactoside and its synthetic derivatives with SARS-CoV 3CLpro: Structure–activity relationship studies reveal salient pharmacophore features 원문보기

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