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Novel anti-Plasmodial hits identified by virtual screening of the ZINC database

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Abstract

Increased resistance of Plasmodium falciparum to most available drugs challenges the control of malaria. Studies with protease inhibitors have suggested important roles for the falcipain family of cysteine proteases. These enzymes act in concert with other proteases to hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. In order to find potential new antimalarial drugs, we screened in silico the ZINC database using two different protocols involving structure- and ligand-based methodologies. Our search identified 19 novel low micromolar inhibitors of cultured chloroquine resistant P. falciparum. The most active compound presented an IC50 value of 0.5 μM against cultured parasites and it also inhibited the cysteine protease falcipain-2 (IC50 = 25.5 μM). These results identify novel classes of antimalarials that are structurally different from those currently in use and which can be further derivatized to deliver leads suitable for optimisation.

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References

  1. WHO (2011) World malaria report 2011, in WHO library cataloguing-in-publication data 2011. World Health Organization WHO, Geneva

    Google Scholar 

  2. Greenwood BM, Fidock DA, Kyle DE, Kappe SHI, Alonso PL, Collins FH, Duffy PE (2008) Malaria: progress, perils, and prospects for eradication. J Clin Invest 118:1266–1276

    Article  CAS  Google Scholar 

  3. Ballou WR (2009) The development of the RTS, S malaria vaccine candidate: challenges and lessons. Parasite Immunol 31(9):492–500

    Article  CAS  Google Scholar 

  4. Wu T, Nagle AS, Chatterjee AK (2011) Road towards new antimalarials—overview of the strategies and their chemical progress. Curr Med Chem 18(6):853–871

    Article  CAS  Google Scholar 

  5. Hyde JE (2002) Mechanisms of resistance of Plasmodium falciparum to antimalarial drugs. Microbes Infect 4(2):165–174

    Article  CAS  Google Scholar 

  6. White NJ (2004) Antimalarial drug resistance. J Clin Invest 113:1084–1092

    CAS  Google Scholar 

  7. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NPJ, Lindegardh N, Socheat D, White NJ (2009) Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 361:455–467

    Article  CAS  Google Scholar 

  8. Ridley RG (2002) Medical need, scientific opportunity and the drive for antimalarial drugs. Nature 415:686–693

    Article  CAS  Google Scholar 

  9. Pink R, Hudson A, Mouries MA, Bendig M (2005) Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov 4:727–740

    Article  CAS  Google Scholar 

  10. Jackson KE, Habib S, Frugier M, Hoen R, Khan S, Pham JS, de Pouplana LR, Royo M, Santos MAS, Sharma A, Ralph SA (2011) Trends Parasitol 27:467–476

    Article  CAS  Google Scholar 

  11. Shenai BR, Sijwali PS, Singh A, Rosenthal PJ (2000) J Biol Chem 275:29000–29010

    Article  CAS  Google Scholar 

  12. Sijwali PS, Shenai BR, Gut J, Singh A, Rosenthal PJ (2001) Biochem J 360:481–489

    Article  CAS  Google Scholar 

  13. Rosenthal PJ (2011) Cysteine proteases of pathogenic organisms. Springer, US, pp 30–48

  14. Shah F, Mukherjee P, Gut J, Legac J, Rosenthal PJ, Tekwani BL, Avery MA (2011) J Chem Inf Model 51(4):852–864

    Article  CAS  Google Scholar 

  15. Rosenthal PJ, Wollish WS, Palmer JT, Rasnick D (1991) J Clin Invest 88:1467–1472

    Article  CAS  Google Scholar 

  16. Rosenthal PJ, Lee GK, Smith RE (1993) J Clin Invest 91:1052–1056

    Article  CAS  Google Scholar 

  17. Rosenthal PJ, Olson JE, Lee GK, Palmer JT, Klaus JL, Rasnick D (1996) Antimicrob Agents Chemother 40:1600–1603

    CAS  Google Scholar 

  18. Verissimo E, Berry N, Gibbons P, Cristiano MLS, Rosenthal PJ, Gut J, Ward SA, O’Neill PM (2008) Bioorg Med Chem Lett 18:4210–4214

    Article  CAS  Google Scholar 

  19. Lee BJ, Singh A, Chiang P, Kemp SJ, Goldman EA, Weinhouse MI, Vlasuk GP, Rosenthal PJ (2003) Antimicrob Agents Chemother 47:3810–3814

    Article  CAS  Google Scholar 

  20. Schulz F, Gelhaus C, Degel B, Vicik R, Heppner S, Breuning A, Leippe M, Gut J, Rosenthal PJ, Scheirmeister T (2007) ChemMedChem 2:1214–1224

    Article  CAS  Google Scholar 

  21. Martichonok V, Plouffe C, Storer A, Ménard R, Jones B (1995) J Med Chem 38:3078–3085

    Article  CAS  Google Scholar 

  22. Micale N, Kozikowski AP, Ettari R, Grasso S, Zappalà M, Jeong J, Kumar A, Hanspal M, Chishti AH (2006) J Med Chem 49:3064–3067

    Article  CAS  Google Scholar 

  23. Ettari R, Micale N, Schirmeister T, Gelhaus C, Leippe M, Nizi E, Di Francesco ME, Grasso S, Zappalà M (2009) J Med Chem 52:2157–2160

    Article  CAS  Google Scholar 

  24. Ettari R, Zappalà M, Micale N, Grazioso G, Giofrè S, Schirmeister T, Grasso S (2011) Eur J Med Chem 46:2058–2065

    Article  CAS  Google Scholar 

  25. Domínguez JN, López S, Charris J, Iarruso L, Lobo G, Semenov A, Olson JE, Rosenthal PJ (1997) J Med Chem 40:2726–2732

    Article  Google Scholar 

  26. Ring CS, Sun E, McKerrow JH, Lee GK, Rosenthal PJ, Kuntz ID, Cohen FE (1993) Proc Natl Acad Sci 90:3583–3587

    Article  CAS  Google Scholar 

  27. Coterón JM, Catterick D, Castro J, Chaparro MJ, Díaz B, Fernández E, Ferrer S, Gamo FJ, Gordo M, Gut J, de las Heras L, Legac J, Marco M, Miguel J, Muñoz V, Porras E, de la Rosa JC, de la Ruiz JR, Sandoval E, Ventosa P, Rosenthal PJ, Fiandor JM (2010) J Med Chem 53:6129–6152

    Article  Google Scholar 

  28. Ekins S, Mestres JJ, Testa B (2007) Br J Pharmacol 152:9–20

    Google Scholar 

  29. Miteva M (2008) Biotechnol Biotechnol Equip 22(1):634–638

    Google Scholar 

  30. Desai PV, Patny A, Gut J, Rosenthal PJ, Tekwani B, Srivastava A, Avery M (2006) J Med Chem 49:1576–1584

    Article  CAS  Google Scholar 

  31. Li H, Huang J, Chen L, Liu X, Chen T, Zhu J, Lu W, Shen X, Li J, Hilgenfeld R, Jiang H (2009) J Med Chem 52:4936–4940

    Article  CAS  Google Scholar 

  32. Kerr ID, Lee JH, Pandey KC, Harrison A, Sajid M, Rosenthal PJ, Brinen LS (2009) J Med Chem 52:852–857

    Article  CAS  Google Scholar 

  33. Jones G, Willett P, Glen RC (1995) J Mol Biol 245:43–53

    Article  CAS  Google Scholar 

  34. Irwin JJ, Schoichet BK (2005) J Chem Inf Model 45:177–182

    Article  CAS  Google Scholar 

  35. Durán A, Zamora I, Pastor M (2009) J Chem Inf Model 49:2129–2138

    Article  Google Scholar 

  36. MOE, Chemical Computing Group Inc Montreal, http://www.chemcomp.com

  37. Shenai BR, Lee BJ, Alvarez-Hernandez A, Chong PY, Emal CD, Neitz RJ, Roush WR, Rosenthal PJ (2003) Antimicrob Agents Chemother 47:154–160

    Article  CAS  Google Scholar 

  38. Desai PV, Patny A, Sabnis Y, Tekwani B, Gut J, Rosenthal PJ, Srivastava A, Avery M (2004) J Med Chem 47:6609–6615

    Article  CAS  Google Scholar 

  39. Chiyanzu I, Hansell E, Gut J, Rosenthal PJ, McKerrow JH, Chibale K (2003) Biooorg Med Chem Lett 13:3527–3530

    Article  CAS  Google Scholar 

  40. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Adv Drug Deliv Rev 23:3–25

    Article  CAS  Google Scholar 

  41. Lipinski CA (2000) J Pharmacol Toxicol Methods 44:235–249

    Article  CAS  Google Scholar 

  42. Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) J Mol Biol 267:727–748

    Article  CAS  Google Scholar 

  43. DeLano WL (1997) The pymol molecular graphic system. DeLano Scientific, Palo Alto

    Google Scholar 

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

    Article  Google Scholar 

  45. Ettari R, Bova F, Zappalà M, Grasso S, Micale N (2010) Med Res Rev 30:136–167

    CAS  Google Scholar 

  46. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) J Comput Chem 30:2785–2791

    Article  CAS  Google Scholar 

  47. Shah F, Gut J, Legac J, Shivakumar D, Sherman W, Rosenthal PJ, Avery MA (2012) J Chem Inf Model 52:696–710

    Article  CAS  Google Scholar 

  48. Teixeira C, Gomes JRB, Gomes P (2011) Curr Med Chem 18:1555–1572

    Article  CAS  Google Scholar 

  49. Kerr ID, Pandey KC, Harrison A, Sajid M, Rosenthal PJ, Brinen LS (2009) J Med Chem 52:852–857

    Article  CAS  Google Scholar 

  50. Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DVS, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF (2010) Nature 465(7296):305–310

    Article  CAS  Google Scholar 

  51. Zhang L, Fourches D, Sedykh A, Zhu H, Golbraikh A, Ekins S, Clark J, Connelly MC, Sigal M, Hodges D, Guiguemde A, Guy RK, Tropsha A (2013) J Chem Inf Model 53(2):475–492

    Article  CAS  Google Scholar 

Download references

Acknowledgments

ASN’s work was financially supported by Fundação para a Ciência e Tecnologia, through the doctoral Grant SFRH/BD/41276/2007. GM’s work was financially supported by the South African National Research Foundation (NRF), Medical Research Council, and University of Cape Town. The University of Cape Town, South African Medical Research Council and South African Research Chairs initiative of the Department of Science and Technology administered through the NRF are gratefully acknowledged for support (KC).

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Authors and Affiliations

  1. Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa

    Grace Mugumbate & Kelly Chibale

  2. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-019, Lisbon, Portugal

    Ana S. Newton, Rui Moreira & Rita C. Guedes

  3. Department of Medicine, San Francisco General Hospital, University of California, San Francisco, Box 0811, San Francisco, CA, 94143, USA

    Philip J. Rosenthal & Jiri Gut

  4. Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, 7701, South Africa

    Kelly Chibale

Authors
  1. Grace Mugumbate
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  2. Ana S. Newton
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  3. Philip J. Rosenthal
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  4. Jiri Gut
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  5. Rui Moreira
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  7. Rita C. Guedes
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Corresponding author

Correspondence to Rita C. Guedes.

Additional information

Grace Mugumbate and Ana S. Newton have equally contributed to this work.

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Mugumbate, G., Newton, A.S., Rosenthal, P.J. et al. Novel anti-Plasmodial hits identified by virtual screening of the ZINC database. J Comput Aided Mol Des 27, 859–871 (2013). https://doi.org/10.1007/s10822-013-9685-z

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  • DOI: https://doi.org/10.1007/s10822-013-9685-z

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