Virtual screening for finding natural inhibitor against cathepsin-L for SARS therapy Article First Online: 29 September 2006 Received: 25 April 2006 Accepted: 08 August 2006 DOI:
Cite this article as: Wang, SQ., Du, QS., Zhao, K. et al. Amino Acids (2007) 33: 129. doi:10.1007/s00726-006-0403-1 Summary.
Recently Simmons et al. reported a new mechanism for SARS virus entry into target cells, where MDL28170 was identified as an efficient inhibitor of CTSL-meditated substrate cleavage with IC
50 of 2.5 nmol/l. Based on the molecule fingerprint searching method, 11 natural molecules were found in the Traditional Chinese Medicines Database (TCMD). Molecular simulation indicates that the MOL376 (a compound derived from a Chinese medicine herb with the therapeutic efficacy on the human body such as relieving cough, removing the phlegm, and relieving asthma) has not only the highest binding energy with the receptor but also the good match in geometric conformation. It was observed through docking studies that the van der Waals interactions made substantial contributions to the affinity, and that the receptor active pocket was too large for MDL21870 but more suitable for MOL736. Accordingly, MOL736 might possibly become a promising lead compound for CTSL inhibition for SARS therapy. Keywords: Severe acute respiratory syndrome (SARS) – MDL28170 – KZ7088 – Molecular simulation – Docking – Structural bioinformatics References Anand, K, Ziebuhr, J, Wadhwani, P, Mesters, JR, Hilgenfeld, R 2003 Coronavirus main proteinase (3CL(pro)) structure: Basis for design of anti-SARS drugs Science 300 1763 1767 PubMed CrossRef Google Scholar Bron, RD, Martin, YC 1996 Use of structure-activity data to compare structure-based clustering: methods and descriptors for use in compound selection J Chem Info Comput Sci 36 572 584 CrossRef Google Scholar Chou, KC 2004a Review: Structural bioinformatics and its impact to biomedical science Curr Med Chem 11 2105 2134 Google Scholar Chou, KC 2004b Modelling extracellular domains of GABA-A receptors: subtypes 1, 2, 3, and 5 Biochem Biophys Res Commun 316 636 642 CrossRef Google Scholar Chou, KC 2004c Insights from modelling three-dimensional structures of the human potassium and sodium channels J Proteome Res 3 856 861 CrossRef Google Scholar Chou, KC 2004d Insights from modelling the tertiary structure of BACE2 J Proteome Res 3 1069 1072 CrossRef Google Scholar Chou, KC 2004e Insights from modelling the 3D structure of the extracellular domain of alpha7 nicotinic acetylcholine receptor Biochem Biophys Res Commun 319 433 438 CrossRef Google Scholar Chou, KC 2005a Coupling interaction between thromboxane A2 receptor and alpha-13 subunit of guanine nucleotide-binding protein J Proteome Res 4 1681 1686 CrossRef Google Scholar Chou, KC 2005b Modeling the tertiary structure of human cathepsin-E Biochem Biophys Res Commun 331 56 60 CrossRef Google Scholar Chou, KC, Howe, WJ 2002 Prediction of the tertiary structure of the beta-secretase zymogen Biochem Biophys Res Commun 292 702 708 PubMed CrossRef Google Scholar Chou, KC, Watenpaugh, KD, Heinrikson, RL 1999 A Model of the complex between cyclin-dependent kinase 5(Cdk5) and the activation domain of neuronal Cdk5 activator Biochem Biophys Res Commun 259 420 428 PubMed CrossRef Google Scholar Chou, KC, Tomasselli, AG, Heinrikson, RL 2000 Prediction of the tertiary structure of a caspase-9/inhibitor complex FEBS Lett 470 249 256 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 Du, QS, Wang, SQ, Jiang, ZQ, Gao, WN, Li, Y, Wei, DQ, Chou, KC 2005 Application of Bioinformatics in search for cleavable peptides of SARS CoV Mpro and chemical modification of octapeptides Med Chem 1 209 213 PubMed CrossRef Google Scholar Ewing, TJ, Makino, S, Skillman, AG, Kuntz, ID 2001 Dock 4.0: search strategies for automated molecular docking of flexible molecule databases J Comput Aided Mol Des 15 411 428 PubMed CrossRef Google Scholar Graham, S, Dhaval, NG, Andrew, JR, Jacqueline, DR, Scott, LD, Paul, B 2005 Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry Proc Natl Acad Sci OSA 102 11876 11881 CrossRef Google Scholar Guan, Y, Zheng, BJ, He, YQ, Liu, XL, Zhuang, ZX, Cheung, CL, Luo, SW, Li, PH, Zhang, LJ, Guan, YJ, et al. 2003 Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China Science 302 276 278 PubMed CrossRef Google Scholar Guncar, G, Pungercic, G, Klemencic, I, Turk, V, Turk, D 1999 Crystal structure of Mhc class II associated P41 II fragment bound to cathepsin L reveals the structural basis for differentiation between cathepsins L and S EMBO J 18 793 803 PubMed CrossRef Google Scholar Jeffrey, H, Diana, Q, Zhong, ZY, Barbara, C 1995 Inhibition of /I-amyloid formation identifies proteolytic precursors and SubceUular site of catabolism Neuron 14 651 659 CrossRef Google Scholar Kakegawa, H 1993 Particapation of cathepsin L in bone resorption FEBS Lett 321 247 250 PubMed CrossRef Google Scholar
Kuntz ID, Demetri TM, Lang PT (2005) DOCK 5.3 User Manual. University of California
Lipinski, CA, Lombardo, F, Dominy, BW, Feeney, PJ 1997 Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv Drug Deliv Rev 23 2 25 CrossRef Google Scholar Mary, E, McGrath, ME 1999 The lysosomal cysteine proteases Annu Rev Biophys Biomol Struct 28 181 204 CrossRef Google Scholar Rota, PA, Oberste, MS, Monroe, SS, Nix, WA, Campagnoli, R, Icenogle, JP, Penaranda, S, Bankamp, B, Maher, K, Chen, MH, et al. 2003 Characterization of a novel coronavirus associated with severe acute respiratory syndrome Science 300 1394 1399 PubMed CrossRef Google Scholar Sheng, XG, Wu, J, Liu, H, Zhang, JI 2004 Studies on the components of the fatty acid of Artemisia annua Grassland Turf 4 68 70 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 Shujaath, M, Michael, RA, Jeffery, SW, Philippe, B 1998 Biochem Biophys Res Commun 157 1117 1123 Google Scholar Wei, DQ, Du, QS, Sun, H, Chou, KC 2006 Insights from modeling the 3D structure of H5N1 influenza virus neuraminidase and its binding interactions with ligands Biochem Biophys Res Commun 344 1048 1055 PubMed CrossRef 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, ZH 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, GP, Troy, FA, 2nd 2003 Characterization by NMR and molecular modeling of the binding of polyisoprenols and polyisoprenyl recognition sequence peptides: 3D structure of the complexes reveals sites of specific interactions Glycobiology 13 51 71 PubMed CrossRef Google Scholar Zhou, GP, Troy, FA, 2nd 2005a NMR study of the preferred membrane orientation of polyisoprenols (dolichol) and the impact of their complex with polyisoprenyl recognition sequence peptides on membrane structure Glycobiology 15 347 359 CrossRef Google Scholar Zhou, GP, Troy, FA 2005b NMR studies on how the binding complex of polyisoprenol recognition sequence peptides and polyisoprenols can modulate membrane structure Curr Protein Peptide Sci 6 399 411 CrossRef Google Scholar Zhou, JJ, Xie, GR, Yan, XJ 2004Traditional chinese medicines: molecular structures, natural sources and applications Chemical Industry Press China Google Scholar