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Probing the structure of Leishmania donovani chagasi DHFR-TS: comparative protein modeling and protein–ligand interaction studies

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Abstract

Dihydrofolate reductase (DHFR) has been used successfully as a drug target in the area of anti-bacterial, anti-cancer and anti-malarial therapy. It also acts as a drug target for Leishmaniasis. Inhibition of DHFR leads to cell death through lack of thymine (nucleotide metabolism). Although the crystal structures of Leishmania major and Trypanosoma cruzi DHFR-thymidylate synthase (TS) have been resolved, to date there is no three-dimensional (3D)-structural information on DHFR-TS of Leishmania donovani chagasi, which causes visceral leishmaniasis. Our aim in this study was to model the 3D structure of L. donovani chagasi DHFR-TS, and to investigate the structural requirements for its inhibition. In this paper we describe a highly refined homology model of L. donovani chagasi DHFR-TS based on available crystallographic structures by using the Homology module of Insight II. Structural refinement and minimization of the generated L. donovani chagasi DHFR-TS model employed the Discover 3 module of Insight II and molecular dynamic simulations. The model was further validated through use of the PROCHECK, Verify_3D, PROSA, PSQS and ERRAT programs, which confirm that the model is reliable. Superimposition of the model structure with the templates L. major A chain, L. major B chain And T. cruzi A chain showed root mean square deviations of 0.69 Å, 0.71 Å and 1.11 Å, respectively. Docking analysis of the L. donovani chagasi DHFR-TS model with methotrexate enabled us to identify specific residues, viz. Val156, Val30, Lys95, Lys75 and Arg97, within the L. donovani chagasi DHFR-TS binding pocket, that play an important role in ligand or substrate binding. Docking studies clearly indicated that these five residues are important determinants for binding as they have strong hydrogen bonding interactions with the ligand.

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References

  1. Cunha AM, Chagas E (1937) New species of protozoa of the genus Leishmania pathogenic to man Leishmania chagasi n. sp previous note. O Hospital 11:3–9

    Google Scholar 

  2. Croft SL, Coombs GH (2003) Leishmaniasis—current chemotherapy and recent advances in the search for novel drugs. Trends Parasitol 19:502–508. doi:10.1016/j.pt.2003.09.008

    Article  CAS  Google Scholar 

  3. Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft Sl, Desjeux P, Wasunna MK, Bryceson ADM (2002) Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis 2:494–501. doi:10.1016/S1473-3099(02)00347-X

    Article  Google Scholar 

  4. Davies CR, Kaye P, Croft SL, Sunder S (2003) Leishmaniasis: new approaches to disease control. BMJ 326:377–382. doi:10.1136/bmj.326.7385.377

    Article  Google Scholar 

  5. Desjeux P (2001) Worldwide increasing risk factors for leishmaniasis. Med Microbiol Immunol 190:77–79. doi:10.1007/s004300100085

    CAS  Google Scholar 

  6. World Health Organization (2000) The Leishmaniasis and Leishmania/HIV co-infections. Fact Sheet Number 116. WHO, Geneva, Switzerland

  7. Shafinaz FC, Villamor VB, Guerrero RH, Leal I, Brun R, Croft SL, Goodman JM, Maes L, Ruiz-Perez LM, Pacanowska DG, Gilbert IH (1999) Design, synthesis, and evaluation of inhibitors of trypanosomal and leishmanial dihydrofolate reductase. J Med Chem 42:4300–4312. doi:10.1021/jm981130+

    Article  Google Scholar 

  8. Decampo R (2001) Recent developments in the chemotherapy of Cha-gas’ disease. Curr Pharm Des 7:1157–1164. doi:10.2174/1381612013397546

    Article  Google Scholar 

  9. McLuskey K, Gibellini F, Carvalho P, Avery MA, Huntera WN (2004) Inhibition of Leishmania major pteridine reductase by 2, 4, 6-triaminoquinazoline: structure of the NADPH ternary complex. Acta Cryst 60:1780–1785. doi:10.1107/S0907444904018955

    Google Scholar 

  10. Ferone R, Roland S (1980) Dihydrofolate reductase: thymidylate synthase, a bifunctional polypeptide from Crithidia fasciculata. Proc Natl Acad Sci USA 77:5802–5806

    Article  CAS  Google Scholar 

  11. Garrett CE, Coderre JA, Meek TD, Garvey EP, Claman DM, Beverly SM, Santhi DV (1984) A Bifunctional thymidylate synthase-dihydrofolate reductase in protozoa. Mol Biochem Parasitol 11:257–265. doi:10.1016/0166-6851(84)90070-7

    Article  CAS  Google Scholar 

  12. Ivanetich KM, Santhi DV (1990) Bifunctional thymidylate synthase-dihydrofolate reductase in protozoa. FASEB J 4:1591–1597. doi:0892-6638/90/0004-1591/$O1.50

    CAS  Google Scholar 

  13. Bermingham A, Derrick JP (2002) The folic acid biosynthesis pathway in bacteria: evaluation of potential for antibacterial drug discovery. BioEssays 24:637–648. doi:10.1002/bies.10114

    Article  CAS  Google Scholar 

  14. Walsh C (2003) Antibiotics: actions, origins, resistance. ASM, Washington. doi:10.1110/ps.041032204

    Google Scholar 

  15. Then RL (2004) Antimicrobial dihydrofolate reductase inhibitors-achievements and future options: review. J Chemother 16:3–12

    CAS  Google Scholar 

  16. Zheng QC, Li ZS, Sun M, Zhang Y, Sun CC (2005) Homology modeling and substrate binding study of nudix hydrolase Ndx1 from Thermos thermophilus HB8. Biochem Biophys Res Commun 333:881–887

    Article  CAS  Google Scholar 

  17. Xu W, Cai P, Yan M, Xu L, Ouyang PK (2007) Molecular docking of xylitol and xylose isomerase from Thermus thermophilus and model analysis. Chem J Chin Univ 28:971–973

    CAS  Google Scholar 

  18. He YP, Hu HR, Xu LS (2005) Structure–activity relationship studies on 6-naphthylmethyl substituted HEPT derivatives as nonnucleoside reverse transcriptase inhibitors based on molecular docking. Chem J Chin Univ 26:254–258

    CAS  Google Scholar 

  19. Knighton DR, Kan CC, Howland E, Janson CA, Hostomska Z, Welsh KM, Matthews DA (1994) Structure of and kinetic channelling in bifunctional dihydrofolate reductase-thymidylate synthase. Nat Struct Biol 1:186–194. doi:10.1038/nsb0394-186

    Article  CAS  Google Scholar 

  20. Senkovich O, Schormann N, Chattopadhyay D (2009) Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate. Acta Cryst 65:704–716. doi:10.1107/S090744490901230X

    Google Scholar 

  21. InsightII (2007) Accelrys, San Diego

  22. GOLD (2006) CCDC, Cambridge

  23. http://www.pymol.org

  24. Needleman SB, Wunsch CD (1970) A general method applicable to the search for similarities in the amino acid sequence of two proteins. J Mol Biol 48:443–453. doi:10.1016/0022-2836(70)90057-4

    Article  CAS  Google Scholar 

  25. Jaroszewski L, Pawlowski K, Godzik A (1998) Multiple model approach: exploring the limits of comparative modeling. J Mol Model 4:294–309. doi:10.1007/s008940050087

    Article  CAS  Google Scholar 

  26. Luthy R, Bowie JU, Eisenberg D (1992) Assessment of protein models with three-dimensional profiles. Nature 356:83–85. doi:10.1038/356083a0

    Article  CAS  Google Scholar 

  27. Colovos C, Yeates TO (1993) Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci 2:1511–1519. doi:10.1002/pro.5560020916

    Article  CAS  Google Scholar 

  28. Hooft RWW, Vriend G, Sander C, Abola EE (1996) Errors in protein structures. Nature 381:272–272. doi:10.1038/381272a0

    Article  CAS  Google Scholar 

  29. Sippl MJ (1993) Boltzmann’s principle, knowledge-based mean fields and protein folding. J Comput Aided Mol Des 7:473–501. doi:10.1007/BF02337562

    Article  CAS  Google Scholar 

  30. Laskowski RA, Macarthur MW, Moss DS, Thornton JM (1993) PROCHECK a program to check the stereo chemical quality of protein structure. J Appl Cryst 26:283–291. doi:10.1107/S0021889892009944

    Article  CAS  Google Scholar 

  31. Guex N, Peitsch MC (1997) SWISS MODEL and the Swiss pdb viewer: an environment for comparative protein modeling. Electrophoresis 18:2714–2723. doi:10.1093/nar/gkg520

    Article  CAS  Google Scholar 

  32. Cerius2 (2006) Accelrys, San Diego

  33. Wallace AC, Laskowski RA, Thornton JM (1995) LIGPLOT: a program to generate schematic diagrams of protein–ligand interactions. Protein Eng 8:127–134. doi:10.1093/protein/8.2.127

    Article  CAS  Google Scholar 

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Acknowledgments

The authors thank the Council for Scientific and Industrial Research (CSIR), New Delhi, India, for providing financial assistance from a grant under Mission Mode Program CMM 0017. We thank Prof. David A. Matthews, Agouron Pharmaceuticals, San Diego, CA, for providing the coordinates of the Leishmania major crystallographic structure. L.M. and P.M. thank CSIR, New Delhi, India, for Project Assistantship.

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  1. Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology (a unit of CSIR), Kolkata, 700032, India

    Lakshmi Maganti, Prabu Manoharan & Nanda Ghoshal

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  1. Lakshmi Maganti
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  2. Prabu Manoharan
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  3. Nanda Ghoshal
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Correspondence to Nanda Ghoshal.

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Maganti, L., Manoharan, P. & Ghoshal, N. Probing the structure of Leishmania donovani chagasi DHFR-TS: comparative protein modeling and protein–ligand interaction studies. J Mol Model 16, 1539–1547 (2010). https://doi.org/10.1007/s00894-010-0649-0

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