From genome to drug lead: identification of a small-molecule inhibitor of the SARS virus.
Virtual screening, a fast, computational approach to identify drug leads [Perola, E.; Xu, K.; Kollmeyer, T. M.; Kaufmann, S. H.; Prendergast, F. G. J. Med. Chem.2000, 43, 401; Miller, M. A. Nat. Rev. Drug Disc.2002, 1 220], is limited by a known challenge in crystallographically determining flexible regions of proteins. This approach has not been able to identify active inhibitors of the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) using solely the crystal structures of a SARS-CoV cysteine proteinase with a flexible loop in the active site [Yang, H. T.; Yang, M. J.; Ding, Y.; Liu, Y. W.; Lou, Z. Y. Proc. Natl. Acad. Sci. U.S.A.2003, 100, 13190; Jenwitheesuk, E.; Samudrala, R. Bioorg. Med. Chem. Lett.2003, 13, 3989; Rajnarayanan, R. V.; Dakshanamurthy, S.; Pattabiraman, N. Biochem. Biophys. Res. Commun.2004, 321, 370; Du, Q.; Wang, S.; Wei, D.; Sirois, S.; Chou, K. Anal. Biochem.2005, 337, 262; Du, Q.; Wang, S.; Zhu, Y.; Wei, D.; Guo, H. Peptides2004, 25, 1857; Lee, V.; Wittayanarakul, K.; Remsungenen, T.; Parasuk, V.; Sompornpisut, P. Science (Asia)2003, 29, 181; Toney, J.; Navas-Martin, S.; Weiss, S.; Koeller, A. J. Med. Chem.2004, 47, 1079; Zhang, X. W.; Yap, Y. L. Bioorg. Med. Chem.2004, 12, 2517]. This article demonstrates a genome-to-drug-lead approach that uses terascale computing to model flexible regions of proteins, thus permitting the utilization of genetic information to identify drug leads expeditiously. A small-molecule inhibitor of SARS-CoV, exhibiting an effective concentration (EC50) of 23 microM in cell-based assays, was identified through virtual screening against a computer-predicted model of the cysteine proteinase. Screening against two crystal structures of the same proteinase failed to identify the 23-microM inhibitor. This study suggests that terascale computing can complement crystallography, broaden the scope of virtual screening, and accelerate the development of therapeutics to treat emerging infectious diseases such as SARS and Bird Flu.
Dooley
Andrea J
AJ
Computer-Aided Molecular Design Laboratory, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Shindo
Nice
N
Taggart
Barbara
B
Park
Jewn-Giew
JG
Pang
Yuan-Ping
YP
D062365:Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D013329:Structure-Activity Relationship
D062365:Aminobenzoates; C509739:CS11 compound; C509740:CS14 compound; D004791:Enzyme Inhibitors; D003546:Cysteine Endopeptidases