Molecular Biology Reports

, Volume 41, Issue 8, pp 5167–5175 | Cite as

An exhaustive yet simple virtual screening campaign against Sortase A from multiple drug resistant Staphylococcus aureus



Methicillin resistant Staphylococcus aureus (MRSA) is one of the challenging bacterial pathogen due to its acquired resistance to the β lactam antibiotics. The Sortase A is an enzyme of Gram-positive bacteria including S. aureus to anchor surface proteins to the cell wall. Sortase A is well studied enzyme and considered as the drug target against MRSA. Sortase A plays active role in anchoring the virulence proteins on the cell wall of the Gram-positive bacteria. The inhibition of Sortase A activity results in the separation of S. aureus from the host cells and ultimately alleviation of the infection. Here, we adapted a structure-based virtual screening protocol which helped in identification of novel potential inhibitors of Sortase A. The protocol involved the docking of a chemical library of druglike compounds with the Sortase A binding site represented by multiple crystal structures. The compounds were ranked by multiple scoring functions and shortlisted for future experimental screening. The method resulted in shortlisting of three compounds as potential novel inhibitors of Sortase A out of a large chemical library. The high rankings of shortlisted compounds estimated by multiple scoring functions showed their binding potential with Sortase A. The results are proved to be a simple yet efficient choice of structure-based virtual screening. The identified compounds are druglike and show high rankings among all set protocols of the virtual screening. We hope that the study would eventually help to expedite the discovery of novel drug candidates against MRSA.


Molecular docking Sortase A Scoring function Enrichment factor Ligand interaction 

Supplementary material

11033_2014_3384_MOESM1_ESM.pdf (324 kb)
Supplementary material 1 (PDF 323 kb)
11033_2014_3384_MOESM2_ESM.pdf (259 kb)
Supplementary material 2 (PDF 258 kb)
11033_2014_3384_MOESM3_ESM.pdf (82 kb)
Supplementary material 3 (PDF 82 kb)
11033_2014_3384_MOESM4_ESM.tif (112 kb)
Supplementary material 4 (TIFF 111 kb)


  1. 1.
    Lowy FD (2003) Antimicrobial resistance: the example of Staphylococcus aureus. J Clin Invest 111:1265–1273PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Diekema DJ, Pfaller MA, Schmitz FJ et al (2001) Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin Infect Dis 32:S114–S132CrossRefPubMedGoogle Scholar
  3. 3.
    Mazmanian SK, Liu G, Ton-That H et al (1999) Staphylococcus aureus sortase, an enzyme that anchors surface proteins to the cell wall. Science 285:760–763CrossRefPubMedGoogle Scholar
  4. 4.
    Paterson GK, Mitchell TJ (2004) The biology of Gram-positive sortase enzymes. Trends Microbiol 12:89–95CrossRefPubMedGoogle Scholar
  5. 5.
    Ton-That H, Marraffini LA, Schneewind O (2004) Protein sorting to the cell wall envelope of Gram-positive bacteria. Mol Cell Res 1694:269–278Google Scholar
  6. 6.
    Schneewind O, Mihaylova-Petkov D, Model P (1993) Cell wall sorting signals in surface proteins of Gram-positive bacteria. EMBO J 12:4803PubMedCentralPubMedGoogle Scholar
  7. 7.
    Schneewind O, Model P, Fischetti VA (1992) Sorting of protein A to the staphylococcal cell wall. Science 70:267–281Google Scholar
  8. 8.
    Navarre WW, Schneewind O (1994) Proteolytic cleavage and cell wall anchoring at the LPXTG motif of surface proteins in Gram positive bacteria. Mol Microbiol 14:115–121CrossRefPubMedGoogle Scholar
  9. 9.
    Perry AM, Ton-That H, Mazmanian SK et al (2002) Anchoring of surface proteins to the cell wall of Staphylococcus aureus III. Lipid II is an in vivo peptidoglycan substrate for sortase-catalyzed surface protein anchoring. J Biol Chem 277:16241–16248CrossRefPubMedGoogle Scholar
  10. 10.
    Ruzin A, Severin A, Ritacco F et al (2002) Further evidence that a cell wall precursor [C55-MurNAc-(peptide)-GlcNAc] serves as an acceptor in a sorting reaction. J Bacteriol 184:2141–2147PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Strominger JL, Izaki K, Matsuhashi M et al (1967) Peptidoglycan transpeptidase and d-alanine carboxypeptidase: penicillin-sensitive enzymatic reactions. Fed Proc 26:9PubMedGoogle Scholar
  12. 12.
    Comfort D, Clubb RT (2004) A comparative genome analysis identifies distinct sorting pathways in Gram-positive bacteria. Infect Immun 72:2710–2722PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Janulczyk R, Rasmussen M (2001) Improved pattern for genome-based screening identifies novel cell wall-attached proteins in Gram-positive bacteria. Infect Immun 69:4019–4026PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Pallen MJ, Lam AC, Antonio M et al (2001) An embarrassment of sortases A richness of substrates? Trends Microbiol 9:97–101CrossRefPubMedGoogle Scholar
  15. 15.
    Maresso AW, Schneewind O (2008) Sortase as a target of anti-infective therapy. Pharmacol Rev 60:128–141CrossRefPubMedGoogle Scholar
  16. 16.
    Suree N, Jung ME, Clubb RT (2007) Recent advances towards new anti-infective agents that inhibit cell surface protein anchoring in Staphylococcus aureus and other Gram-positive pathogens. Mini Rev Med Chem 7:991–1000CrossRefPubMedGoogle Scholar
  17. 17.
    Oh K-B, Nam K-W, Ahn H et al (2010) Therapeutic effect of (Z)-3-(2, 5-dimethoxyphenyl)-2-(4-methoxyphenyl) acrylonitrile (DMMA) against 〈i〉 Staphylococcus aureus 〈/i〉 infection in a murine model. Biochem Biophys Res Commun 396:440–444CrossRefPubMedGoogle Scholar
  18. 18.
    Chang S, Sievert DM, Hageman JC et al (2003) Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene. New Engl J Med 348:1342–1347CrossRefPubMedGoogle Scholar
  19. 19.
    Klevens RM, Morrison MA, Nadle J et al (2007) Invasive methicillin-resistant Staphylococcus aureus infections in the United States. J Am Med Assoc 298:1763–1771CrossRefGoogle Scholar
  20. 20.
    Waldvogel FA (1999) New resistance in Staphylococcus aureus. New Engl J Med 340:556–557CrossRefPubMedGoogle Scholar
  21. 21.
    Chambers HF (2001) The changing epidemiology of Staphylococcus aureus? Infect Dis 7:178CrossRefGoogle Scholar
  22. 22.
    Talbot GH, Bradley J, Edwards JE et al (2006) Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin Infect Dis 42:657–668CrossRefPubMedGoogle Scholar
  23. 23.
    Chenna BC, Shinkre BA, King JR et al (2008) Identification of novel inhibitors of bacterial surface enzyme Staphylococcus aureus Sortase A. Bioorg Med Chem Lett 18:380–385CrossRefPubMedGoogle Scholar
  24. 24.
    BABEL O (2010) OEChem v (2010) OpenEye Scientific Software, Inc. (Santa Fe, NM, USA,
  25. 25.
    MayaChemTools MayaChemTools (
  26. 26.
    Suree N, Yi SW, Thieu W et al (2009) Discovery and structure-activity relationship analysis of Staphylococcus aureus sortase A inhibitors. Bioorg Med Chem 17:7174–7185PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    FRED (2010) OpenEye Scientific Software, Inc. (Santa Fe, NM, USA,
  28. 28.
    Stahl M, Rarey M (2001) Detailed analysis of scoring functions for virtual screening. J Med Chem 44:1035–1042CrossRefPubMedGoogle Scholar
  29. 29.
    UlHaq Z, Uddin R, Gul S (2011) Optimization of structure based virtual screening protocols against thymidine monophosphate kinase inhibitors as antitubercular agents. Mol Inf 30:851–862CrossRefGoogle Scholar
  30. 30.
    McGann M (2012) FRED and HYBRID docking performance on standardized datasets. J Comput Aided Mol Des 26:897–906CrossRefPubMedGoogle Scholar
  31. 31.
    McGann M (2011) FRED pose prediction and virtual screening accuracy. J Chem Inf Model 51:578–596CrossRefPubMedGoogle Scholar
  32. 32.
    Pencheva T, Soumana OS, Pajeva I et al (2010) Post-docking virtual screening of diverse binding pockets: comparative study using DOCK, AMMOS, X-score and FRED scoring functions. Eur J Med Chem 45:2622–2628CrossRefPubMedGoogle Scholar
  33. 33.
    Zong Y, Bice TW, Ton-That H et al (2004) Crystal structures of Staphylococcus aureus sortase A and its substrate complex. J Biol Chem 279:31383–31389CrossRefPubMedGoogle Scholar
  34. 34.
    Martinez-Hackert E, Anikeeva N, Kalams SA et al (2006) Structural basis for degenerate recognition of natural HIV peptide variants by cytotoxic lymphocytes. J Biol Chem 281:20205–20212CrossRefPubMedGoogle Scholar
  35. 35.
    CLCSequence (2013) CLC sequence viewer vers. 6.3 (CLC bio, Aarhus, Denmark)Google Scholar
  36. 36.
    Kitchen DB, Decornez H, Furr JR et al (2004) Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Disc 3:935–949CrossRefGoogle Scholar
  37. 37.
    Li Y, Kim DJ, Ma W et al (2011) Discovery of novel checkpoint kinase 1 inhibitors by virtual screening based on multiple crystal structures. J Chem Inf Mod 51:2904–2914CrossRefGoogle Scholar
  38. 38.
    Schulz-Gasch T, Stahl M (2003) Binding site characteristics in structure-based virtual screening: evaluation of current docking tools. J Mol Mod 9:47–57Google Scholar
  39. 39.
    Race PR, Bentley ML, Melvin JA et al (2009) Crystal structure of Streptococcus pyogenes Sortase A implications for sortase mechanism. J Biol Chem 284:6924–6933PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Pala D, Beuming T, Sherman W et al (2013) Structure-based virtual screening of MT2 melatonin receptor: influence of template choice and structural refinement. J Chem Inf Mod 53:821–835CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological SciencesUniversity of KarachiKarachiPakistan

Personalised recommendations