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A computational workflow for the design of irreversible inhibitors of protein kinases

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Abstract

Design of irreversible inhibitors is an emerging and relatively less explored strategy for the design of protein kinase inhibitors. In this paper, we present a computational workflow that was specifically conceived to assist such design. The workflow takes the form of a multi-step procedure that includes: the creation of a database of already known reversible inhibitors of protein kinases, the selection of the most promising scaffolds that bind one or more desired kinase templates, the modification of the scaffolds by introduction of chemically reactive groups (suitable cysteine traps) and the final evaluation of the reversible and irreversible protein–ligand complexes with molecular dynamics simulations and binding free energy predictions. Most of these steps were automated. In order to prove that this is viable, the workflow was tested on a database of known inhibitors of ERK2, a protein kinase possessing a cysteine in the ATP site. The modeled ERK2-ligand complexes and the values of the estimated binding free energies of the putative ligands provide useful indicators of their aptitude to bind reversibly and irreversibly to the protein kinase. Moreover, the computational data are used to rank the ligands according to their computed binding free energies and their ability to bind specific protein residues in the reversible and irreversible complexes, thereby providing a useful decision-making tool for each step of the design. In this work we present the overall procedure and the first proof of concept results.

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References

  1. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) Science (New York, N.Y) 298:1912–1934

    CAS  Google Scholar 

  2. Krause DS, Van Etten RA (2005) New Engl J Med 353:172–187

    Article  CAS  Google Scholar 

  3. Liao JJ (2007) J Med Chem 50:409–424

    Article  CAS  Google Scholar 

  4. Margutti S, Laufer SA (2007) Chem Med Chem 2:1116–1140

    CAS  Google Scholar 

  5. Bikker JA, Brooijmans N, Wissner A, Mansour TS (2009) J Med Chem 52:1493–1509

    Article  CAS  Google Scholar 

  6. Ohori M, Kinoshita T, Yoshimura S, Warizaya M, Nakajima H, Miyake H (2007) Biochem Biophys Res Commun 353:633–637

    Article  CAS  Google Scholar 

  7. Wissner A, Fraser HL, Ingalls CL, Dushin RG, Floyd MB, Cheung K, Nittoli T, Ravi MR, Tan X, Loganzo F (2007) Bioorg Med Chem 15:3635–3648

    Article  CAS  Google Scholar 

  8. Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T, Zhao F, Vincent PW, Naumov GN, Bradner JE, Althaus IW, Gandhi L, Shapiro GI, Nelson JM, Heymach JV, Meyerson M, Wong KK, Janne PA (2007) Cancer Res 67:11924–11932

    Article  CAS  Google Scholar 

  9. Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC, Mendonca RV, Sweeney MD, Scott KC, Grothaus PG, Jeffery DA, Spoerke JM, Honigberg LA, Young PR, Dalrymple SA, Palmer JT (2007) Chem Med Chem 2:58–61

    CAS  Google Scholar 

  10. Cohen MS, Zhang C, Shokat KM, Taunton J (2005) Science (New York, N.Y) 308:1318–1321

    CAS  Google Scholar 

  11. Potashman MH, Duggan ME (2009) J Med Chem 52:1232–1246

    Article  CAS  Google Scholar 

  12. Robertson JG (2005) Biochemistry 44:5561–5571

    Article  CAS  Google Scholar 

  13. Knight ZA, Shokat KM (2005) Chem Biol 12:621–637

    Article  CAS  Google Scholar 

  14. Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, McGinnis JP, Wissner A, Sharma SV, Isselbacher KJ, Settleman J, Haber DA (2005) Proc Natl Acad Sci USA 102:7665–7670

    Article  CAS  Google Scholar 

  15. Zhang JM, Yang PL, Gray NS (2009) Nat Rev Cancer 9:28–39

    Article  CAS  Google Scholar 

  16. Schirmer A, Kennedy J, Murli S, Reid R, Santi DV (2006) Proc Natl Acad Sci USA 103:4234–4239

    Article  CAS  Google Scholar 

  17. Rastelli G, Rosenfeld R, Reid R, Santi DV (2008) J Struct Biol 164:18–23

    Article  CAS  Google Scholar 

  18. Ohori M, Kinoshita T, Okubo M, Sato K, Yamazaki A, Arakawa H, Nishimura S, Inamura N, Nakajima H, Neya M, Miyake H, Fujii T (2005) Biochem Biophys Res Commun 336:357–363

    Article  CAS  Google Scholar 

  19. Blair JA, Rauh D, Kung C, Yun CH, Fan QW, Rode H, Zhang C, Eck MJ, Weiss WA, Shokat KM (2007) Nat Chem Biol 3:229–238

    Article  CAS  Google Scholar 

  20. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) J Comput Chem 25:1605–1612

    Article  CAS  Google Scholar 

  21. Case DA, Cheatham TE 3rd, Darden T, Gohlke H, Luo R, Merz KM Jr, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) J Comput Chem 26:1668–1688

    Article  CAS  Google Scholar 

  22. Case DA, Darden TA, Cheatham TE III, Simmerling CL, Wang J, Duke RE, Luo R, Merz KM, Pearlman DA, Crowley M, Walker RC, Zhang W, Wang B, Hayik S, Roitberg A, Seabra G, Wong KF, Paesani F, Wu X, Brozell S, Tsui V, Gohlke H, Yang L, Tan C, Mongan J, Hornak V, Cui G, Mathews DH, Schafmeiste C, Ross WS, Kollman PA (2006) AMBER. University of California, San Francisco CA

    Google Scholar 

  23. Ferrari AM, Degliesposti G, Sgobba M, Rastelli G (2007) Bioorg Med Chem 15:7865–7877

    Article  CAS  Google Scholar 

  24. Rastelli G, Degliesposti G, Del Rio A, Sgobba M (2009) Chem Biol Drug Des 73:283–286

    Article  CAS  Google Scholar 

  25. Rastelli G, Del Rio A, Degliesposti G, Sgobba M (2010) J Comput Chem 31:797–810

    CAS  Google Scholar 

  26. Stoica I, Sadiq SK, Coveney PV (2008) J Am Chem Soc 130:2639–2648

    Article  CAS  Google Scholar 

  27. Kuhn B, Gerber P, Schulz-Gasch T, Stahl M (2005) J Med Chem 48:4040–4048

    Article  CAS  Google Scholar 

  28. Del Rio A, Baldi BF, Rastelli G (2009) Chem Biol Drug Des 74:630–635

    Article  CAS  Google Scholar 

  29. Brown SP, Muchmore SW (2007) J Chem Inf Model 47:1493–1503

    Article  CAS  Google Scholar 

  30. Lyne PD, Lamb ML, Saeh JC (2006) J Med Chem 49:4805–4808

    Article  CAS  Google Scholar 

  31. Waterhouse AM, Procter JB, Martin DM, Clamp M, Barton GJ (2009) Bioinformatics (Oxford, England) 25:1189–1191

    Article  CAS  Google Scholar 

  32. Katayama N, Orita M, Yamaguchi T, Hisamichi H, Kuromitsu S, Kurihara H, Sakashita H, Matsumoto Y, Fujita S, Niimi T (2008) Proteins 73:795–801

    Article  CAS  Google Scholar 

  33. Kinoshita T, Warizaya M, Ohori M, Sato K, Neya M, Fujii T (2006) Bioorg Med Chem Lett 16:55–58

    Article  CAS  Google Scholar 

  34. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) J Comput Chem 25:1157–1174

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from AIRC, the Italian Association for Cancer Research (Research grant “Novel irreversible protein kinase inhibitors targeting a conserved active site cysteine”).

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Correspondence to Giulio Rastelli.

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Del Rio, A., Sgobba, M., Parenti, M.D. et al. A computational workflow for the design of irreversible inhibitors of protein kinases. J Comput Aided Mol Des 24, 183–194 (2010). https://doi.org/10.1007/s10822-010-9324-x

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  • DOI: https://doi.org/10.1007/s10822-010-9324-x

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