Amino Acids

, Volume 33, Issue 1, pp 129–135

Virtual screening for finding natural inhibitor against cathepsin-L for SARS therapy

  • S.-Q. Wang
  • Q.-S. Du
  • K. Zhao
  • A.-X. Li
  • D.-Q. Wei
  • K.-C. Chou
Article
  • 157 Downloads

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 IC50 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 

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References

  1. Anand, K, Ziebuhr, J, Wadhwani, P, Mesters, JR, Hilgenfeld, R 2003Coronavirus main proteinase (3CL(pro)) structure: Basis for design of anti-SARS drugsScience30017631767PubMedCrossRefGoogle Scholar
  2. Bron, RD, Martin, YC 1996Use of structure-activity data to compare structure-based clustering: methods and descriptors for use in compound selectionJ Chem Info Comput Sci36572584CrossRefGoogle Scholar
  3. Chou, KC 2004aReview: Structural bioinformatics and its impact to biomedical scienceCurr Med Chem1121052134Google Scholar
  4. Chou, KC 2004bModelling extracellular domains of GABA-A receptors: subtypes 1, 2, 3, and 5Biochem Biophys Res Commun316636642CrossRefGoogle Scholar
  5. Chou, KC 2004cInsights from modelling three-dimensional structures of the human potassium and sodium channelsJ Proteome Res3856861CrossRefGoogle Scholar
  6. Chou, KC 2004dInsights from modelling the tertiary structure of BACE2J Proteome Res310691072CrossRefGoogle Scholar
  7. Chou, KC 2004eInsights from modelling the 3D structure of the extracellular domain of alpha7 nicotinic acetylcholine receptorBiochem Biophys Res Commun319433438CrossRefGoogle Scholar
  8. Chou, KC 2005aCoupling interaction between thromboxane A2 receptor and alpha-13 subunit of guanine nucleotide-binding proteinJ Proteome Res416811686CrossRefGoogle Scholar
  9. Chou, KC 2005bModeling the tertiary structure of human cathepsin-EBiochem Biophys Res Commun3315660CrossRefGoogle Scholar
  10. Chou, KC, Howe, WJ 2002Prediction of the tertiary structure of the beta-secretase zymogenBiochem Biophys Res Commun292702708PubMedCrossRefGoogle Scholar
  11. Chou, KC, Watenpaugh, KD, Heinrikson, RL 1999A Model of the complex between cyclin-dependent kinase 5(Cdk5) and the activation domain of neuronal Cdk5 activatorBiochem Biophys Res Commun259420428PubMedCrossRefGoogle Scholar
  12. Chou, KC, Tomasselli, AG, Heinrikson, RL 2000Prediction of the tertiary structure of a caspase-9/inhibitor complexFEBS Lett470249256PubMedCrossRefGoogle Scholar
  13. Chou, KC, Wei, DQ, Zhong, WZ 2003Binding mechanism of coronavirus main proteinase with ligands and its implication to drug design against SARS.Biochem Biophys Res Commun308148151Erratum: ibid., 2003, Vol. 310, 675PubMedCrossRefGoogle Scholar
  14. Du, QS, Wang, SQ, Jiang, ZQ, Gao, WN, Li, Y, Wei, DQ, Chou, KC 2005Application of Bioinformatics in search for cleavable peptides of SARS CoV Mpro and chemical modification of octapeptidesMed Chem1209213PubMedCrossRefGoogle Scholar
  15. Ewing, TJ, Makino, S, Skillman, AG, Kuntz, ID 2001Dock 4.0: search strategies for automated molecular docking of flexible molecule databasesJ Comput Aided Mol Des15411428PubMedCrossRefGoogle Scholar
  16. Graham, S, Dhaval, NG, Andrew, JR, Jacqueline, DR, Scott, LD, Paul, B 2005Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entryProc Natl Acad Sci OSA1021187611881CrossRefGoogle Scholar
  17. Guan, Y, Zheng, BJ, He, YQ, Liu, XL, Zhuang, ZX, Cheung, CL, Luo, SW, Li, PH, Zhang, LJ, Guan, YJ,  et al. 2003Isolation and characterization of viruses related to the SARS coronavirus from animals in southern ChinaScience302276278PubMedCrossRefGoogle Scholar
  18. Guncar, G, Pungercic, G, Klemencic, I, Turk, V, Turk, D 1999Crystal structure of Mhc class II associated P41 II fragment bound to cathepsin L reveals the structural basis for differentiation between cathepsins L and SEMBO J18793803PubMedCrossRefGoogle Scholar
  19. Jeffrey, H, Diana, Q, Zhong, ZY, Barbara, C 1995Inhibition of /I-amyloid formation identifies proteolytic precursors and SubceUular site of catabolismNeuron14651659CrossRefGoogle Scholar
  20. Kakegawa, H 1993Particapation of cathepsin L in bone resorptionFEBS Lett321247250PubMedCrossRefGoogle Scholar
  21. Kuntz ID, Demetri TM, Lang PT (2005) DOCK 5.3 User Manual. University of CaliforniaGoogle Scholar
  22. Lipinski, CA, Lombardo, F, Dominy, BW, Feeney, PJ 1997Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settingsAdv Drug Deliv Rev23225CrossRefGoogle Scholar
  23. Mary, E, McGrath, ME 1999The lysosomal cysteine proteasesAnnu Rev Biophys Biomol Struct28181204CrossRefGoogle Scholar
  24. Rota, PA, Oberste, MS, Monroe, SS, Nix, WA, Campagnoli, R, Icenogle, JP, Penaranda, S, Bankamp, B, Maher, K, Chen, MH,  et al. 2003Characterization of a novel coronavirus associated with severe acute respiratory syndromeScience30013941399PubMedCrossRefGoogle Scholar
  25. Sheng, XG, Wu, J, Liu, H, Zhang, JI 2004Studies on the components of the fatty acid of Artemisia annuaGrassland Turf46870Google Scholar
  26. Sheridan, RP, Miller, MD, Underwood, DJ, Kearsley, SK 1996Chemical similarity using geometric atom pair descriptorsJ Chem Info Comput Sci36128136CrossRefGoogle Scholar
  27. Shujaath, M, Michael, RA, Jeffery, SW, Philippe, B 1998Biochem Biophys Res Commun15711171123Google Scholar
  28. Wei, DQ, Du, QS, Sun, H, Chou, KC 2006Insights from modeling the 3D structure of H5N1 influenza virus neuraminidase and its binding interactions with ligandsBiochem Biophys Res Commun34410481055PubMedCrossRefGoogle Scholar
  29. 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 2003The crystal structures of severe acute respiratory syndrome virus main protease and its complex with an inhibitorProc Natl Acad Sci USA1001319013195PubMedCrossRefGoogle Scholar
  30. Zhou, GP, Troy, FA,2nd 2003Characterization by NMR and molecular modeling of the binding of polyisoprenols and polyisoprenyl recognition sequence peptides: 3D structure of the complexes reveals sites of specific interactionsGlycobiology135171PubMedCrossRefGoogle Scholar
  31. Zhou, GP, Troy, FA,2nd 2005aNMR study of the preferred membrane orientation of polyisoprenols (dolichol) and the impact of their complex with polyisoprenyl recognition sequence peptides on membrane structureGlycobiology15347359CrossRefGoogle Scholar
  32. Zhou, GP, Troy, FA 2005bNMR studies on how the binding complex of polyisoprenol recognition sequence peptides and polyisoprenols can modulate membrane structureCurr Protein Peptide Sci6399411CrossRefGoogle Scholar
  33. Zhou, JJ, Xie, GR, Yan, XJ 2004Traditional chinese medicines: molecular structures, natural sources and applicationsChemical Industry PressChinaGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • S.-Q. Wang
    • 1
  • Q.-S. Du
    • 2
    • 5
  • K. Zhao
    • 1
  • A.-X. Li
    • 3
  • D.-Q. Wei
    • 4
    • 5
  • K.-C. Chou
    • 5
  1. 1.College of Pharmaceuticals and BiotechnologyTianjin UniversityTianjinChina
  2. 2.Institute of Bioinformatics and Drug DiscoveryTianjin Normal UniversityTianjinChina
  3. 3.Tianjin Wujing Medical InstituteTianjinChina
  4. 4.College of Life Science and TechnologyShanghai Jiaotong UniversityShanghaiChina
  5. 5.Gordon Life Science InstituteSan DiegoU.S.A.

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