Skip to main content
SpringerLink
Log in

Modeling the inhibition of quadruple mutant Plasmodium falciparum dihydrofolate reductase by pyrimethamine derivatives

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

Modeling studies were performed on known inhibitors of the quadruple mutant Plasmodium falciparum dihydrofolate reductase (DHFR). GOLD was used to dock 32 pyrimethamine derivatives into the active site of DHFR obtained from the x-ray crystal structure 1J3K.pdb. Several scoring functions were evaluated and the Molegro Protein-Ligand Interaction Score was determined to have one of the best correlation to experimental pK i . In conjunction with Protein-Ligand Interaction scores, predicted binding modes and key protein-ligand interactions were evaluated and analyzed in order to develop criteria for selecting compounds having a greater chance of activity versus resistant strains of Plasmodium falciparum. This methodology will be used in future studies for selection of compounds for focused screening libraries.

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
Fig. 8

Similar content being viewed by others

References

  1. National Center for Infectious Diseases, Division of Parasitic Diseases (2007) Internet references. Retrieved from http://www.cdc.gov/malaria/facts.htm 11/4/2006

  2. Wells J (2005) Retrieved from http://www.sfgate.com/cgi-bin/article.cgi?file=/c/a/2005/06/05/CMG3NCLBKA1.DTL 4/1/2007

  3. WHO Publication (2003) Retrieved from http://www.rbm.who.int/amd2003/amr2003/pdf/ch2.pdf 4/1/2007

  4. Hyde JE (2002) Microbes Infect 4:165

    Article  CAS  Google Scholar 

  5. Yuthavong Y (2002) Microbes Infect 4:175

    Article  CAS  Google Scholar 

  6. Sibley CH, Ringwald P (2006) Malar J 5:48

    Article  Google Scholar 

  7. Ferone R (1977) Bull World Health Organ 55:291

    CAS  Google Scholar 

  8. Huennekens FM (1994) Adv Enzyme Regul 34:397

    Article  CAS  Google Scholar 

  9. Rollo IM (1970) CRC Crit Rev Clin Lab Sci 1:565

    Article  CAS  Google Scholar 

  10. Yuvaniyama J, Chitnumsub P, Kamchonwongpaison S, Vanichtanankul J, Sirawaraporn W, Taylor P, Walkinshaw M, Yuthavong Y (2003) Nat Struct Biol 10:357

    Article  CAS  Google Scholar 

  11. Sirawaraporn W, Sathikul T, Sirawaraporn R, Yuthavong Y, Santi DV (1997) Proc Natl Acad Sci USA 94:1124

    Article  CAS  Google Scholar 

  12. Kongsaeree P, Khongsuk P, Leartsakulpanich U, Chitnumsub P, Tarnchombpoo B, Walkinshaw MD, Yuthavong Y (2005) Proc Natl Acad Sci USA 102:13046

    Article  CAS  Google Scholar 

  13. Mehlin C (2005) Comb Chem High Throughput Screen 8:5

    Article  CAS  Google Scholar 

  14. Brady RL, Cameron A (2004) Curr Drug Targets 5:137

    Article  CAS  Google Scholar 

  15. Delfino RT, Santos-Filho OA, Figueroa-Villar JD (2002) Biophys Chem 98:287

    Article  CAS  Google Scholar 

  16. Kamchonwongpaison S, Quarrell R, Charoensetakul N, Ponsinet R, Vilaivan T, Vanichtanankul J, Tarnchampoo W, Sirawaraporn W, Lowe G, Yuthavong Y (2004) J Med Chem, 47:673

    Article  Google Scholar 

  17. Parenti MD, Pacchioni S, Ferrari AM, Rastelli G (2004) J Med Chem 47:4258

    Article  CAS  Google Scholar 

  18. Agrawal VK, Sohgaura R, Khadikar PV (2002) Bioorg Med Chem 10:2919

    Article  CAS  Google Scholar 

  19. Mattioni BE, Jurs PC (2003) J Mol Graph Model 21:391

    Article  CAS  Google Scholar 

  20. Gangjee A, Lee X (2005) J Med Chem 48:1448

    Article  CAS  Google Scholar 

  21. Sutherland JJ, Weaver DF (2004) J Comput Aided Drug Des 18:309

    Article  CAS  Google Scholar 

  22. Ganjee A, Lin X (2005) J Med Chem 48:1448

    Article  Google Scholar 

  23. Santos-Filho OA, Hopfinger AJ (2001) J Comput Aided Mol Des 15:1

    Article  CAS  Google Scholar 

  24. Chiu T-L, So S-S (2004) J Chem Inf Comput Sci 44:154

    Article  CAS  Google Scholar 

  25. Hunt SY, Detering C, Varani G, Jacobus DP, Schiehser GA, Shieh H-M, Nevchas I, Terpinski J, Sibley CH (2005) Mol Biochem Parasitol 144:198

    Article  CAS  Google Scholar 

  26. Bissantz C, Folkers G, Rognan D (2000) J Med Chem 43:4759

    Article  CAS  Google Scholar 

  27. Wang R, Lai L, Wang S (2002) J Comput-Aided Mol Des 16:11

    Article  CAS  Google Scholar 

  28. Wang R, Liu L, Lai L, Tang Y (1998) J Mol Model 4:379

    Article  CAS  Google Scholar 

  29. Warren GL et al (2006) J Med Chem 49:5912

    Article  CAS  Google Scholar 

  30. Kitchen DB et al (2004) Nat Rev Drug Discov 3:935

    Article  CAS  Google Scholar 

  31. Teodoro ML, Kavraki LE (2003) Curr Pharm Des 9:1635

    Article  CAS  Google Scholar 

  32. Cavasotto CN, Abagyan RA (2004) J Mol Biol 337:209

    Article  CAS  Google Scholar 

  33. Guex N, Peitsch MC (1997) Electrophoresis 18:2714

    Article  CAS  Google Scholar 

  34. Molecular Operation Environment. MOE Molecular Operating Environment, Chemical Computing Group, Montreal, Quebec, Canada (2005) Retrieved from http://www.chemcomp.com 4/1/2007

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

    Article  CAS  Google Scholar 

  36. Chemdraw, Cambridgesoft, Inc., Cambridge, MA (2007) Retrieved from http://www.camsoft.com 4/1/2007

  37. Halgren TA (1996) J Comp Chem 17:490

    Article  CAS  Google Scholar 

  38. Thomsen R, Christensen MH (2006) J Med Chem 49:3315

    Article  CAS  Google Scholar 

  39. Krammer A, Kirchhoff PD, Jiang X, Venkatachalam CM, Waldman M (2005) J Mol Graph Model 23:395

    Article  CAS  Google Scholar 

  40. Gehlhaar DK, Verkhivker GM, Rejto PA, Sherman CJ, Fogel DB, Fogel LJ, Freer ST (1995) Chem Biol 2:317

    Article  CAS  Google Scholar 

  41. Gehlhaar DK, Bouzida D, Rejto PA, In: Parrill L, Rami Reddy M (eds), Rational drug design: novel methodology and practical applications, American Chemical Society, Washington, DC (1999), 292

  42. Jain AN (1996) J Comput Aided Mol Des 10:427

    Article  CAS  Google Scholar 

  43. Muegge I, Martin YCA (1999) J Med Chem 42:791

    Article  CAS  Google Scholar 

  44. Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) J Comp Chem 4:187

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work is supported by the US Army Medical Research and MaterielCommand under Contract No. W81XWH-06-C-0399. The views, opinions and/or findings contained in this report are those of the authors and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation.

Author information

Authors and Affiliations

  1. Natural Selection, Inc., 9330 Scranton Road, Suite 150, San Diego, CA, 92121, USA

    Gary B. Fogel & Mars Cheung

  2. Southwestern College, 900 Otay Lakes Road, Chula Vista, CA, 91910, USA

    Eric Pittman & David Hecht

Authors
  1. Gary B. Fogel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mars Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric Pittman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Hecht
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Hecht.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fogel, G.B., Cheung, M., Pittman, E. et al. Modeling the inhibition of quadruple mutant Plasmodium falciparum dihydrofolate reductase by pyrimethamine derivatives. J Comput Aided Mol Des 22, 29–38 (2008). https://doi.org/10.1007/s10822-007-9152-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-007-9152-9

Keywords

Search

Navigation