title: Virtual screening identification of novel severe acute respiratory syndrome 3C-like protease inhibitors and in vitro confirmation.
abstract: 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 308307 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 IC(50) 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.
authors.affiliation: School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Thi Thanh Hanh
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Hwa-Ja
authors.initials: HJ
authors.lastname: Ryu
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Soonwook
authors.initials: S
authors.lastname: Hwang
authors.forename: Vincent
authors.initials: V
authors.lastname: Breton
authors.forename: Joon Haeng
authors.initials: JH
authors.lastname: Rhee
authors.forename: Doman
authors.initials: D
authors.lastname: Kim
mesh_terms: D000086042:3C Viral Proteases; D001667:Binding, Competitive; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000235:genetics; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000187:drug effects*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects* / Q000201:enzymology; D054852:Small Molecule Libraries; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D011480:Protease Inhibitors; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases