title: Virtual screening of novel noncovalent inhibitors for SARS-CoV 3C-like proteinase.
abstract: The SARS coronavirus 3C-like proteinase is considered as a potential drug design target for the treatment of severe acute respiratory syndrome (SARS). Owing to the lack of available drugs for the treatment of SARS, the discovery of inhibitors for SARS coronavirus 3C-like proteinase that can potentially be optimized as drugs appears to be highly desirable. We have built a "flexible" three-dimensional model for SARS 3C-like proteinase by homology modeling and multicanonical molecular dynamics method and used the model for virtual screening of chemical databases. After Dock procedures, strategies including pharmocophore model, consensus scoring, and "drug-like" filters were applied in order to accelerate the process and improve the success rate of virtual docking screening hit lists. Forty compounds were purchased and tested by HPLC and colorimetric assay against SARS 3C-like proteinase. Three of them including calmidazolium, a well-known antagonist of calmodulin, were found to inhibit the enzyme with an apparent K(i) from 61 to 178 microM. These active compounds and their binding modes provide useful information for understanding the binding sites and for further selective drug design against SARS and other coronavirus.
authors.affiliation: State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Liu
authors.forename: Changkang
authors.initials: C
authors.lastname: Huang
authors.forename: Keqiang
authors.initials: K
authors.lastname: Fan
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Shiyong
authors.initials: S
authors.lastname: Liu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Pei
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D017076:Computer-Aided Design; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry; D007093:Imidazoles / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D007093:Imidazoles; D011480:Protease Inhibitors; D014764:Viral Proteins; C031938:calmidazolium; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases