Skip to main content
SpringerLink
Log in

Computer-aided molecular design of 1H-imidazole-2,4-diamine derivatives as potential inhibitors of Plasmodium falciparum DHFR enzyme

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Design and discovery of new potential inhibitors of Plasmodium falciparum dihydrofolate reductase (PfDHFR), equally active against both the wild-type and mutant strains, is urgently needed. In this study, a computer-aided molecular design approach that involved ab initio molecular orbital and density functional theory calculations, along with molecular electrostatic potential analysis, and molecular docking studies was employed to design 15 1H-imidazole-2,4-diamine derivatives as potential inhibitors of PfDHFR enzyme. Visual inspection of the binding modes of the compounds demonstrated that they all interact, via H-bond interactions, with key amino acid residues (Asp54, Ileu/Leu164, Asn/Ser108 and Ile14) similar to those of WR99210 (3) in the active site of the enzymes used in the study. These interactions are known to be essential for enzyme inhibition. These compounds showed better or comparable binding affinities to that of the bound ligand (WR99210). In silico toxicity predictions, carried out using TOPKAT software, also indicated that the compounds are non-toxic.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Schenell JR, Dyson HJ, Wright PE (2004) Structure, dynamics, and catalytic function of dihydrofolate reductase. Annu Rev Biophys Biomol Struct 33:119–140

    Article  Google Scholar 

  2. Nzila A (2006) Inhibitors of de novo folate enzymes in P. falciparum. Drug Discov Today 11:939–944

    Article  CAS  Google Scholar 

  3. Anderson AC, Wright DL (2005) Targeting DHFR in parasitic protozoa. Drug Discov Today 10:121–128

    Article  CAS  Google Scholar 

  4. Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI (2005) The global distribution of clinical episodes of P. falciparum malaria. Nature 434:214–217

    Article  CAS  Google Scholar 

  5. Lemcke T, Christensen IT, Jorgensen FS (1999) Towards understanding of drug resistance in malaria: three-dimensional structure of P. falciparum DHFR by homology building. Bioorg Med Chem 7:1003–1011

    Article  CAS  Google Scholar 

  6. Rastelli G, Sirawaraporn W, Sompornpisut P, Vilaivan T, Kamchonwongpaisan S, Quarrell R, Lowe G, Thebtaranonth Y, Yuthavong Y (2000) Interaction of pyrimethamine, cycloguanil, WR99210 and their analogues with P. falciparum dihydrofolate reductase: structural basis of antifolate. Bioorg Med Chem 8:1117–1128

    Article  CAS  Google Scholar 

  7. Delfino RT, Santos-Filho OA, Figueroa-Villar JD (2002) Molecular modeling of wild-type and antifolate resistant mutant P. falciparum DHFR. Biophys Chem 98:287–300

    Article  CAS  Google Scholar 

  8. Santos-Filho OA, de Alencastrob RD, Figueroa-Villar JD (2001) Homology modeling of wild-type and pyrimethamine/cycloguanil-cross-resistant mutant type P. falciparum DHFR: a model for antimalarial chemotherapy resistance. Biophys Chem 91:305–317

    Article  CAS  Google Scholar 

  9. Yuvaniyama J, Chitnumsub P, Kamchonwongpaisan S, Vanichatanankul J, Sirawaraporn W, Taylor P, Walkinshaw MD, Yuthavong Y (2003) Insights into antifolate resistance from malarial DHFR-TS structures. Nat Struct Biol 10:357–365

    Article  CAS  Google Scholar 

  10. Sirawaraporn W, Sathitkul T, Sirawaraporn R, Yuthavong Y, Santi DV (1997) Antifolate-resistant mutants of P. falciparum dihydrofolate reductase. Proc Natl Acad Sci USA 94:1124–1129

    Article  CAS  Google Scholar 

  11. Warhurst DV (1998) Antimalarial drug discovery: development of inhibitors of dihydrofolate reductase active in drug resistance. Drug Discov Today 3:538–546

    Article  CAS  Google Scholar 

  12. Legesse A, Bharatam PV (2009) 3D-QSAR analysis of cycloguanil derivatives as inhibitors of Dihydrofolate reductase enzyme from Cycloguanil-resistant strain (T9/94) of P. falciparum: CoMFA and CoMSIA studies. J Mol Graph Model 28:357–367

    Article  Google Scholar 

  13. Hecht D, Cheung M, Fogel GB (2008) QSAR using evolved neural networks for the inhibition of mutant PfDHFR by pyrimethamine derivatives. BioSystems 92:10–15

    Article  CAS  Google Scholar 

  14. Maitarad P, Saparpakorn P, Hannongbua S, Kamchonwongpaisan S, Tarnchompoo B, Yuthavong Y (2009) Particular interaction between pyrimethamine derivatives and quadruple mutant type dihydrofolate reductase of P. falciparum: CoMFA and quantum chemical calculations studies. J Enzyme Inhib Med Chem 24:471–479

    Article  CAS  Google Scholar 

  15. Maitarad P, Kamchonwongpaisan S, Vanichtanankul J, Vilaivan T, Yuthavong Y, Hannongbua S (2009) Interactions between cycloguanil derivatives and wild type and resistance-associated mutant P. falciparum dihydrofolate reductases. J Comput Aided Mol Des 23:241–252

    Article  CAS  Google Scholar 

  16. Delfino RT, Santos-Filho OA, Figuar-Villar JD (2002) Type 2 antifolates in the chemotherapy of falciparum malaria. J Braz Chem Soc 13:727–741

    Article  CAS  Google Scholar 

  17. Legesse A, Bharatam PV (2008) Modelling and informatics in the analysis of P. falciparum DHFR enzyme inhibitors. Curr Med Chem 15:1552–1569

    Article  Google Scholar 

  18. McKie JH, Douglas KT, Chan C, Roser SA, Yates R, Read M, Hyde JE, Dascombe MJ, Yuthavong Y, Sirawaraporn W (1998) Rational drug design approach for the overcoming drug resistance: application to pyrimethamine resistance in malaria. J Med Chem 41:1367–1370

    Article  CAS  Google Scholar 

  19. Sardarian A, Douglas KT, Read M, Sims PF, Hyde JE, Chitnumsub P, Sirawaraporn R, Sirawaraporn W (2003) Pyrimethamine analogs as strong inhibitors of double and quadruple mutants of dihydrofolate reductase in human malaria. J Biol Chem 1:960–964

    CAS  Google Scholar 

  20. Kamchonwongpaisan S, Quarrell R, Charoensetakul N, Ponsinet R, Vilaivan T, Vanichtanankul J, Tarnchompoo B, Sirawaraporn W, Lowe G, Yuthavong Y (2004) Inhibitors of multiple mutants of P. falciparum dihydrofolate reductase and their antimalarial activities. J Med Chem 47:673–680

    Article  CAS  Google Scholar 

  21. Yuthavong Y, Vilainvan T, Chareonsethakul N, Kamchonwongpaisan S, Sirawaraporn W, Quarrell R, Lowe G (2000) Development of a lead inhibitor for the A16V + S108T mutant of dihydrofolate reductase from the cycloguanil-resistant strain (T9/94) of P. falciparum. J Med Chem 43:2738–2744

    Article  CAS  Google Scholar 

  22. Sichaiwat C, Intaraudom C, Kamchonwongpaisan S, Vanichtanankul J, Thebtaranonth Y, Yuthavong Y (2004) Target guided synthesis of 5-benzyl-2, 4-diamonopyrimidines: their antimalarial activities and binding affinities to wild type and mutant dihydrofolate reductases from P. falciparum. J Med Chem 47:345–354

    Article  Google Scholar 

  23. Hunt SY, Detering C, Varani G, Jacobus DP, Schiehser GA, Shieh HM, Nevchas I, Terpinski J, Sibley CH (2005) Identification of the optimal third generation antifolate against P. falciparum and P. vivax. Mol Biochem Parasitol 144:198–205

    Article  CAS  Google Scholar 

  24. Japrung D, Leartsakulpanich U, Chusacultanachai S, Yuthavong Y (2007) Conflicting requirements of P. falciparum dihydrofolate reductase mutations conferring resistance to pyrimethamine-WR99210 combination. Antimicrob Agents Chemother 51:4356–4360

    Article  CAS  Google Scholar 

  25. Legesse A, Patel DS, Bharatam PV (2010) Shape- and chemical feature-based virtual screening: identification of leads as potential inhibitors of PfDHFR enzyme. Chem Biol Drug Des 75:115–126

    Article  Google Scholar 

  26. Bhattacharjee AK, Nichols DA, Gerena L, Roncal N, Gutteridge CE (2007) An in silico 3D pharmacophore model of chalcones useful in the design of novel antimalarial agents. Med Chem 3:317–326

    Article  CAS  Google Scholar 

  27. França TC, Wilter A, Ramalho TC, Pascutti PG, Figueroa-Villar JD (2006) Molecular dynamics of the interaction of Plasmodium falciparum and human serine hydroxymethyltransferase with 5-formyl-6-hydrofolic acid analogues: design of new potential antimalarials. J Braz Chem Soc 17:1383–1392

    Article  Google Scholar 

  28. Dasgupta T, Chitnumsub P, Kamchonwongpaisan S, Maneeruttanarungroj C, Nichols SE, Lyons TM, Tirado-Rives J, Jorgensen WL, Yuthavong Y, Anderson KS (2009) Exploiting structural analysis, in silico screening, and serendipity to identify novel inhibitors of drug-resistant falciparum malaria. ACS Chem Biol 4:29–40

    Article  CAS  Google Scholar 

  29. Desai PV, Patny A, Gut J, Rosenthal PJ, Tekwani B, Srivastava A, Avery M (2006) Identification of novel parasitic cysteine protease inhibitors by use of virtual screening. 2. The available chemical directory. J Med Chem 49:1576–1584

    Article  CAS  Google Scholar 

  30. Hehre WJ, Radom L, Schleyer PV, Pople JA (1995) Ab initio molecular orbital theory. Wiley, New York

    Google Scholar 

  31. Forseman JB, Frisch AE (1998) Exploring chemistry with electronic structure methods. Gaussian, Pittsburg

    Google Scholar 

  32. Par RG, Yang W (1989) Density functional theory of atoms and molecules. Oxford University Press, New York

    Google Scholar 

  33. Bartolotti LJ, Fluchick K (1996) In: Lipkowitz KB (ed) Reviews in computational chemistry. VCH, New York

    Google Scholar 

  34. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JJA, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2004) Gaussian 03, Revision C.02. Gaussian Inc, Wallingford. http://www.gaussian.com

  35. Becke AD (1993) Density functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  36. Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B37:785–789

    Google Scholar 

  37. Perdew JP, Wang Y (1992) Accurate and simple analytic representation of the electron-gas correlation energy. Phys Rev B45:13244–13249

    Google Scholar 

  38. Scott AP, Radom L (1996) Harmonic vibrational frequencies: an evaluation of Hartree-Fock, Møller-Plesset, Quadratic configuration interaction, density functional theory, and semiempirical scale factors. J Chem Phys 100:16502–16513

    Article  CAS  Google Scholar 

  39. Barone V, Cossi M (1998) Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent model. J Phys Chem 102:1995–2001

    CAS  Google Scholar 

  40. Hehre WJ (2001) A guide to molecular mechanics and quantum chemical calculations. Wavefunction, Irvine

    Google Scholar 

  41. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749

    Article  CAS  Google Scholar 

  42. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 47:1750–1759

    Article  CAS  Google Scholar 

  43. SYBYL 7.1 (2005) Tripos, St Louis, MO

  44. http://accelrys.com/products/discovery-studio/toxicology/index.html (Accessed on 2 January, 2010)

  45. Taft CA, da Silva VB, da Silva CHT (2008) Current topics in computer-aided drug design. J Pharm Sci 97:1089–1098

    Article  CAS  Google Scholar 

  46. Song CM, Lim SJ, Tong JC (2009) Recent advances in computer-aided drug design. Briefings Bioinform 10:579–591

    Article  CAS  Google Scholar 

  47. Kapetanovic IM (2008) Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach. Chem Biol Interact 171:165–176

    Article  CAS  Google Scholar 

  48. Patel DS, Bharatam PV (2009) Novel +N(←L)2 species with two lone pairs on nitrogen: systems isoelectronic to carbodicarbenes. Chem Commun 2009:1064–1066

  49. Bharatam PV, Patel DS, Iqbal P (2005) Pharmacophoric features of biguanidienes: an electronic structure study. J Med Chem 48:7615–7622

    Article  CAS  Google Scholar 

  50. Bharatam PV, Sundriyal S (2006) Molecular electrostatic potentials in the design of dendrimers for the delivery of glitazones. J Nanosci Nanotechnol 6:3277–3282

    Article  CAS  Google Scholar 

  51. Roy DK, Balanarayan P, Gadre SR (2009) Signatures of molecular recognition from the topography of electrostatic potential. J Chem Sci 121:815–821

    Article  CAS  Google Scholar 

  52. Rastelli G, Pacchioni S, Sirawaraporn W, Sirawaraporn R, Parenti MD, Ferrari AM (2003) Docking and database screening reveal new classes of P. falciparum dihydrofolate reductase inhibitors. J Med Chem 46:2834–2845

    Article  CAS  Google Scholar 

  53. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25

    Article  CAS  Google Scholar 

  54. Vistoli G, Pedretti A, Testa B (2008) Assessing drug likeness—what we are missing? Drug Discov Today 13:285–294

    Article  CAS  Google Scholar 

  55. Li AP (2004) Accurate prediction of human drug toxicity: a major challenge in drug development. Chem Biol Interact 150:3–7

    Article  CAS  Google Scholar 

  56. Drug withdrawals. http://www.ganfyd.org. (Accessed 25 December 2009)

  57. Chattopadhyay R, Mahajan B, Kumar S (2007) Assessment of safety of the major antimalarial drugs. Expert Opin Drug Safety 6:505–521

    Article  CAS  Google Scholar 

  58. Alkadi HO (2007) Antimalarial drug toxicity. Chemotherapy 53:385–391

    Article  CAS  Google Scholar 

  59. Gifford E, van de Waterbeemd H (2003) ADMET in silico modeling: towards prediction paradasie? Nat Rev Drug Discov 2:192–204

    Article  Google Scholar 

  60. Merlot C (2010) Computational toxicology: a tool for early safety evaluation. Drug Discov Today 15:16–22

    Article  CAS  Google Scholar 

  61. Prival MJ (2001) Evaluation of the TOPKAT system for predicting the carcinogenicity of chemicals. Environ Mol Mutagen 37:55–69

    Article  CAS  Google Scholar 

  62. Richard AM (1998) Commercial toxicology prediction systems: a regulatory perspective. Toxicol Lett 102:611–616

    Article  Google Scholar 

  63. TOPKAT Version 6.2. User Guide (2004) Accelrys, San Diego

  64. Genther CS, Schoeny RS, Loper JC, Smith CC (1977) Mutagenic studies of folic acid antagonists. Antimicrob Agents Chemother 12:84–92

    CAS  Google Scholar 

  65. Mui EJ, Schiehser GA, Milhous WK, Hsu H, Roberts CW, Kirisits M, Muench S, Rice D, Dubey JP, Fowble JW, Rathod PK, Queener SF, Liu SR, Jacobus DP, McLeod R (2008) Novel Triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo. PLoS Negl Trop Dis 2:e190. doi:10.1371/journal.pntd.0000190

    Article  Google Scholar 

  66. Canfield CJ, Milhous WK, Ager AL, Rossan RN, Sweeney TR, Lewis NJ, Jacobus DP (1993) PS-15: a potent, orally active antimalarial from a new class of folic acid antagonists. Am J Trop Med Hyg 49:121–126

    CAS  Google Scholar 

Download references

Acknowledgement

L.A. thanks The Government of Federal Democratic Republic of Ethiopia for financial support.

Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar-160 062, Mohali, Punjab, India

    Legesse Adane & Prasad V. Bharatam

Authors
  1. Legesse Adane
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prasad V. Bharatam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Prasad V. Bharatam.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Adane, L., Bharatam, P.V. Computer-aided molecular design of 1H-imidazole-2,4-diamine derivatives as potential inhibitors of Plasmodium falciparum DHFR enzyme. J Mol Model 17, 657–667 (2011). https://doi.org/10.1007/s00894-010-0756-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-010-0756-y

Keyword

Search

Navigation