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Molecular docking and 3D-quantitative structure activity relationship analyses of peptidyl vinyl sulfones: Plasmodium Falciparum cysteine proteases inhibitors

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Abstract

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were conducted on a series (39 molecules) of peptidyl vinyl sulfone derivatives as potential Plasmodium Falciparum cysteine proteases inhibitors. Two different methods of alignment were employed: (i) a receptor-docked alignment derived from the structure-based docking algorithm GOLD and (ii) a ligand-based alignment using the structure of one of the ligands derived from a crystal structure from the PDB databank. The best predictions were obtained for the receptor-docked alignment with a CoMFA standard model (q 2 = 0.696 and r 2 = 0.980) and with CoMSIA combined electrostatic, and hydrophobic fields (q 2 = 0.711 and r 2 = 0.992). Both models were validated by a test set of nine compounds and gave satisfactory predictive r 2 pred values of 0.76 and 0.74, respectively. CoMFA and CoMSIA contour maps were used to identify critical regions where any change in the steric, electrostatic, and hydrophobic fields may affect the inhibitory activity, and to highlight the key structural features required for biological activity. Moreover, the results obtained from 3D-QSAR analyses were superimposed on the Plasmodium Falciparum cysteine proteases active site and the main interactions were studied. The present work provides extremely useful guidelines for future structural modifications of this class of compounds towards the development of superior antimalarials.

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References

  1. Das MK, Lumb V, Mittra P, Singh SS, Dash AP, Sharma YD (2010) J Antimicrob Chemother 65(6):1258

    Article  CAS  Google Scholar 

  2. Martin RE, Kirk K (2004) Mol Biol Evol 21(10):1938

    Article  CAS  Google Scholar 

  3. Wiesner J, Ortmann R, Jomaa H, Schlitzer M (2003) Angewandte Chemie 42(43):5274

    Article  CAS  Google Scholar 

  4. Sachs J, Malaney P (2002) Nature 415(6872):680

    Article  CAS  Google Scholar 

  5. Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, Paulsen IT, James K, Eisen JA, Rutherford K, Salzberg SL, Craig A, Kyes S, Chan MS, Nene V, Shallom SJ, Suh B, Peterson J, Angiuoli S, Pertea M, Allen J, Selengut J, Haft D, Mather MW, Vaidya AB, Martin DM, Fairlamb AH, Fraunholz MJ, Roos DS, Ralph SA, McFadden GI, Cummings LM, Subramanian GM, Mungall C, Venter JC, Carucci DJ, Hoffman SL, Newbold C, Davis RW, Fraser CM, Barrell B (2002) Nature 419(6906):498

    Article  CAS  Google Scholar 

  6. Padmanaban G (2003) Adv Biochem Eng/Biotechnol 84:123

    Article  CAS  Google Scholar 

  7. Teixeira C, Gomes JR, Gomes P (2011) Curr Med Chem 18(10):1555

    Article  CAS  Google Scholar 

  8. Rosenthal PJ, Sijwali PS, Singh A, Shenai BR (2002) Curr Pharm Des 8(18):1659

    Article  CAS  Google Scholar 

  9. Rosenthal PJ (2004) Int J Parasitol 34(13–14):1489

    Article  CAS  Google Scholar 

  10. Subramanian S, Hardt M, Choe Y, Niles RK, Johansen EB, Legac J, Gut J, Kerr ID, Craik CS, Rosenthal PJ (2009) PloS one 4(4):e5156

    Article  Google Scholar 

  11. Batra S, Sabnis YA, Rosenthal PJ, Avery MA (2003) Bioorg Med Chem 11(10):2293

    Article  CAS  Google Scholar 

  12. Rosenthal PJ, Olson JE, Lee GK, Palmer JT, Klaus JL, Rasnick D (1996) Antimicrob Agents Chemother 40(7):1600

    CAS  Google Scholar 

  13. Singh A, Rosenthal PJ (2001) Antimicrob Agents Chemother 45(3):949

    Article  CAS  Google Scholar 

  14. Ettari R, Bova F, Zappala M, Grasso S, Micale N (2010) Med Res Rev 30(1):136

    CAS  Google Scholar 

  15. Olson JE, Lee GK, Semenov A, Rosenthal PJ (1999) Bioorg Med Chem 7(4):633

    Article  CAS  Google Scholar 

  16. Shenai BR, Lee BJ, Alvarez-Hernandez A, Chong PY, Emal CD, Neitz RJ, Roush WR, Rosenthal PJ (2003) Antimicrob Agents Chemother 47(1):154

    Article  CAS  Google Scholar 

  17. MarvinSketch 5.2.2, 2009, ChemAxon (http://www.chemaxon.com)

  18. Sybyl X 1.3, Tripos Software, St. Louis, USA

  19. Jones G, Willett P, Glen RC (1995) J Mol Biol 245(1):43

    Article  CAS  Google Scholar 

  20. Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) J Mol Biol 267(3):727

    Article  CAS  Google Scholar 

  21. Kerr ID, Lee JH, Pandey KC, Harrison A, Sajid M, Rosenthal PJ, Brinen LS (2009) J Med Chem 52(3):852

    Article  CAS  Google Scholar 

  22. Case DA, Darden TA, Cheatham TE, Simmerling CLI, Wang J, Duke RE, Luo R, Crowley M, Walker RC, Zhang W, Merz KM, Wang B, Hayik S, Roitberg A, Seabra G, Kolossváry KF, Wong KF, Paesani F, Vanicek F, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Yang L, Tan C, Mongan J, Hornak V, Cui G, Mathews DH, Seetin MG, Sagui C, Babin V, Kollman PA (2008) AMBER 10. University of California, San Francisco

    Google Scholar 

  23. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, Yang R, Cieplak P, Luo R, Lee T, Caldwell J, Wang J, Kollman P (2003) J Comput Chem 24(16):1999

    Article  CAS  Google Scholar 

  24. Kerr ID, Lee JH, Farady CJ, Marion R, Rickert M, Sajid M, Pandey KC, Caffrey CR, Legac J, Hansell E, McKerrow JH, Craik CS, Rosenthal PJ, Brinen LS (2009) J Biol Chem 284(38):25697

    Article  CAS  Google Scholar 

  25. Holm L, Park J (2000) Bioinformatics 16(6):566

    Article  CAS  Google Scholar 

  26. Perkins R, Fang H, Tong W, Welsh WJ (2003) Environ Toxicol Chem/SETAC 22(8):1666

    Article  CAS  Google Scholar 

  27. Golbraikh A, Tropsha A (2002) J Mol Graph Model 20(4):269

    Article  CAS  Google Scholar 

  28. Saxena AK, Prathipati P (2003) SAR QSAR Environ Res 14(5–6):433

    Article  CAS  Google Scholar 

  29. Gramatica P (2004) Evaluation of different statistical approaches for the validation of quantitative structure-activity relationships. Final report for JRC Contract ECVA-CCR.496576-Z. European Chemicals Bureau, Joint Research Centre, European Commission, Ispra, Italy

  30. Bohm M, Sturzebecher J, Klebe G (1999) J Med Chem 42(3):458

    Article  CAS  Google Scholar 

  31. Mittal RR, McKinnon RA, Sorich MJ (2008) J Mol Model 14(1):59

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful for the financial support from Fundação para a Ciência e a Tecnologia (FCT, Portugal) to CIQ-UP and CICECO, for the Program Ciência 2007 and for the Post-doctoral fellowship SFRH/BPD/62967/2009 awarded to Cátia Teixeira. We also thank FCT and the European Union (FEDER) for funding through Project refs. PTDC/QUI/65142/2006 and FCOMP-01-0124-FEDER-007418, respectively.

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Authors and Affiliations

  1. Centro de Investigação em Química da Universidade do Porto, Departamento de Química, Faculdade de Ciências, Universidade do Porto, R. Campo Alegre, 687, 4169-007, Porto, Portugal

    Cátia Teixeira & Paula Gomes

  2. CICECO, Universidade de Aveiro, Campus Universitário de Santiago, 3810-193, Aveiro, Portugal

    Cátia Teixeira & José R. B. Gomes

  3. ITODYS, University Paris 7, CNRS UMR 7086, 15 rue Jean Antoine de Baif, 75205, Paris Cedex13, France

    Thierry Couesnon

Authors
  1. Cátia Teixeira
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  2. José R. B. Gomes
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  3. Thierry Couesnon
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  4. Paula Gomes
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Correspondence to Cátia Teixeira.

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Teixeira, C., Gomes, J.R.B., Couesnon, T. et al. Molecular docking and 3D-quantitative structure activity relationship analyses of peptidyl vinyl sulfones: Plasmodium Falciparum cysteine proteases inhibitors. J Comput Aided Mol Des 25, 763–775 (2011). https://doi.org/10.1007/s10822-011-9459-4

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