Anti-SARS drug screening by molecular docking Article First Online: 22 May 2006 Received: 05 September 2005 Accepted: 01 February 2006 DOI:
Cite this article as: Wei, DQ., Zhang, R., Du, QS. et al. Amino Acids (2006) 31: 73. doi:10.1007/s00726-006-0361-7 Summary.
Starting from a collection of 1386 druggable compounds obtained from the 3D pharmacophore search, we performed a similarity search to narrow down the scope of docking studies. The template molecule is KZ7088 (Chou et al., 2003,
Biochem Biophys Res Commun 308: 148–151). The MDL MACCS keys were used to fingerprint the molecules. The Tanimoto coefficient is taken as the metric to compare fingerprints. If the similarity threshold was 0.8, a set of 50 unique hits and 103 conformers were retrieved as a result of similarity search. The AutoDock 3.011 was used to carry out molecular docking of 50 ligands to their macromolecular protein receptors. Three compounds, i.e., C 28H 34O 4N 7Cl, C 21H 36O 5N 6, and C 21H 36O 5N 6, were found that may be promising candidates for further investigation. The main feature shared by these three potential inhibitors as well as the information of the involved side chains of SARS Cov Mpro may provide useful insights for the development of potent inhibitors against SARS enzyme. Keywords: SARS CoV Mpro – KZ7088 – Molecular docking – Similarity search – Inhibitor design References Anand, K, Ziebuhr, J, Wadhwani, P, Mesters, JR, Hilgenfeld, R 2003 Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs Science 300 1763 1767 PubMed CrossRef Google Scholar Anfinsen, CG 1973 Principles that govern folding of protein chains Science 181 223 230 PubMed Google Scholar Brown, RD, Martin, YC 1996 Use of structure-activity data to compare structure-based clustering. Methods and descriptors for use in compound selection J Chem Inf Comput Sci 36 572 584 CrossRef Google Scholar Chen, L-L, Ou, H-Y, Zhang, R, Zhang, C-T 2003 ZCURVE_CoV: a new system to recognize protein coding genes in coronavirus genomes, and its applications in analyzing SARS-CoV genomes Biochem Biophys Res Commun 307 382 388 PubMed CrossRef Google Scholar Chou, KC 1975 Studies on the enzyme kinetics of the cavity-active site Acta Biochimica Biophys Sin 7 95 103 Google Scholar Chou, KC 1976 The kinetics of the combination reaction between enzyme and substrate Sci Sin 19 505 528 Google Scholar Chou, KC 1992 Energy-optimized structure of antifreeze protein and its binding mechanism J Mol Biol 223 509 517 PubMed CrossRef Google Scholar Chou, KC 2004 Review: structural bioinformatics and its impact to biomedical science Curr Med Chem 11 2105 2134 PubMed Google Scholar Chou, KC, Carlacci, L 1991 Simulated annealing approach to the study of protein structures Protein Eng 4 661 667 PubMed Google Scholar Chou, KC, Jiang, SP 1974 Studies on the rate of diffusion-controlled reactions of enzymes Sci Sin 17 664 680 Google Scholar Chou, KC, Pottle, M, Nemethy, G, Ueda, Y, Scheraga, HA 1982 Structure of beta-sheets: origin of the right-handed twist and of the increased stability of antiparallel over parallel sheets J Mol Biol 162 89 112 PubMed CrossRef Google Scholar Chou, KC, Scheraga, HA 1982 Origin of the right-handed twist of beta-sheets of poly-L-valine chains Proc Natl Acad Sci USA 79 7047 7051 PubMed CrossRef Google Scholar Chou, KC, Wei, DQ, Zhong, WZ 2003 Binding mechanism of coronavirus main proteinase with ligands and its implication to drug design against SARS Biochem Biophys Res Commun 308 148 151 PubMed CrossRef Google Scholar Chou, KC, Zhou, GP 1982 Role of the protein outside active site on the diffusion-controlled reaction of enzyme J Am Chem Soc 104 1409 1413 CrossRef Google Scholar Drosten, C, Gunther, S, Preiser, W, van der Werf, S, Brodt, HR, Becker, S, Rabenau, H, Panning, M, Kolesnikova, L, Fouchier, RA 2003 Identification of a novel coronavirus in patients with severe acute respiratory syndrome N Engl J Med 348 1967 1976 PubMed CrossRef Google Scholar Du, Q, Wang, S, Wei, DQ, Sirois, S, Chou, KC 2005a Molecular modelling and chemical modification for finding peptide inhibitor against SARS CoV Mpro Anal Biochem 337 262 270 CrossRef Google Scholar Du, QS, Wang, SQ, Jiang, ZQ, Gao, WN, Li, YD, Wei, DQ, Chou, KC 2005b Application of bioinformatics in search for cleavable peptides of SARS-CoV Mpro and chemical modification of octapeptides Med Chem 1 209 213 CrossRef Google Scholar Gao, F, Ou, H-Y, Chen, L-L, Zheng, W-X, Zhang, C-T 2003 Prediction for proteinase cleavage sitess in polyproteins of coronaviruses and its applications in analyzing SARS-CoV genomes FEBS Lett 553 451 456 PubMed CrossRef Google Scholar Ksiazek, TG, Erdman, D, Goldsmith, CS, Zaki, SR, Peret, T, Emery, S, Tong, S, Urbani, C, Comer, JA, Lim, W 2003 A novel coronavirus associated with severe acute respiratory syndrome N Engl J Med 348 1953 1966 PubMed CrossRef Google Scholar Miura, HS, Nakagaki, K, Taguchi, F 2004 N-terminal domain of the murine coronavirus receptor CEACAM1 is responsible for fusogenic activation and conformational changes of the spike protein J Virol 78 216 223 PubMed CrossRef Google Scholar Morris, GM, Goodsell, DS, Halliday, RS, Huey, R, Hart, WE, Belew, RK, Olson, AJ 1988 Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function J Comput Chem 19 1639 1662 CrossRef Google Scholar Rayer, M 2002 Geometric problems and algorithms in computer-aided molecular design Thomas, L eds. Bioinformatics from genomes to drugs Wiley-VCH Weinheim 318 319 Google Scholar Sheridan, RP, Miller, MD, Underwood, DJ, Kearsley, SK 1996 Chemical similarity using geometric atom pair descriptors J Chem Info Comput Sci 36 128 136 CrossRef Google Scholar Shortridge, KF 2003 Severe acute respiratory syndrome and influenza: virus incursions from southern China Am J Respir Crit Care Med 168 1416 1420 PubMed CrossRef Google Scholar Sirois, S, Wei, DQ, Du, Q, Chou, KC 2004 Virtual screening for SARS-CoV protease based on KZ7088 pharmacophore points J Chem Inf Comput Sci 44 1111 1122 PubMed CrossRef Google Scholar Sirois, S, Hatzakis, GE, Wei, DQ, Du, Q, Chou, KC 2005 Assessment of chemical libraries for their druggability Comput Biol Chem 29 55 67 PubMed CrossRef Google Scholar Tanford, C 1962 Contribution of hydrophobic interactions to the stability of the globular conformation of proteins J Am Chem Soc 84 4240 4274 CrossRef Google Scholar Vaidyanathan, J, Vaidyanathan, TK, Yadav, P 2001 Collagen-ligand interaction in dentinal adhesion: computer visualization and analysis Linaras Biomat 22 2911 2920 CrossRef Google Scholar Xiong, B, Gui, CS, Xu, XY, Luo, C, Chen, J, Luo, HB, Chen, LL, Li, GW, Sun, T, Yu, CY, Yue, LD, Duan, WH, Shen, JK, Qin, L, Shi, TL, Li, YX, Chen, KX, Luo, XM, Shen, X, Shen, JH, Jiang, HL 2003 Acta Pharmacol Sin 24 497 PubMed Google Scholar Yang, H, Yang, M, Ding, Y, Liu, Y, Lou, Z, Zhou, Z, Sun, L, Mo, L, Ye, S, Pang, H, Gao, GF, Anand, K, Bartlam, M, Hilgenfeld, R, Rao, Z 2003 The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitor Proc Natl Acad Sci USA 100 13190 13195 PubMed CrossRef Google Scholar Zhou, GQ, Zhong, WZ 1982 Diffusion-controlled reactions of enzymes. A comparison between Chou’s model and Alberty-Hammes-Eigen’s model Eur J Biochem 128 383 387 PubMed CrossRef Google Scholar Zhou, ZP, Li, TT, Chou, KC 1982 The flexibility during the juxtaposition of reacting groups and the upper limits of enzyme reactions Biophys Chem 14 277 281 CrossRef Google Scholar