Skip to main content

Advertisement

Springer Nature Link
Log in

Molecular modeling studies, synthesis, and biological evaluation of Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR) inhibitors

  • Full Length Paper
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

The search for new antimalarial agents is necessary as current drugs in the market become vulnerable due to the emergence of resistance strains of Plasmodium falciparum (P. falciparum). The biosynthetic pathway for fatty acids has been recognized and validated as an important drug target in P.falciparum. One of the important enzymes in this pathway that has a determinant role in completing the cycles of chain elongation is Enoyl-ACP reductase (ENR) also popularly known as FabI. In this paper we report the design, synthesis, and microbial evaluation of inhibitors of Plasmodium enoyl reductase (PfENR). The search for inhibitors involved a virtual screening of the iResearch database with docking simulations. One of the hits was selected and modified to optimize its binding to PfENR; this resulted in the development of analogues of N-benzylidene-4-phenyl-1,3-thiazol-2-amine. The activity of these analogues was predicted from comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models constructed from a dataset of 43 known inhibitors of PfENR. The most promising molecules were synthesized and their structures characterized by spectroscopic techniques. The molecules were screened for in vitro antimalarial activity by whole-cell assay method. Two molecules, viz. VRC-007 and VRC-009, were found to be active at 4.67 and 7.01 μM concentrations, respectively.

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

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  1. Breman JG (2001) The ears of the hippopotamus: manifestations, determinants and estimates of the malaria burden. Am J Trop Med Hyg 64: 1–11

    PubMed  CAS  Google Scholar 

  2. Breman JG, Egan A, Keusch GT (2001) The intolerable burden of malaria: a new look at the numbers. Am J Trop Med Hyg 64: v–vii

    Google Scholar 

  3. Ridley RG (2002) Medical need, scientific opportunity and the drive for antimalarial drugs. Nature 415: 686–693. doi:10.1038/415686a

    Article  PubMed  CAS  Google Scholar 

  4. Heath RJ, Rock CO (1995) Enoyl-acyl carrier protein reductase (fabI) plays a determinant role in completing cycles of fatty acid elongation in Escherichia coli. J Biol Chem 270: 26538–26542. doi:10.1074/jbc.270.44.26538

    Article  PubMed  CAS  Google Scholar 

  5. Lu JZ, Lee PJ, Waters NC, Prigge ST (2005) Fatty acid synthesis as a target for antimalarial drug discovery. Comb Chem High Throughput Screen 8: 15–26. doi:10.2174/1386207053328192

    Article  PubMed  CAS  Google Scholar 

  6. Marrakchi H, Zhang YM, Rock CO (2002) Mechanistic diversity and regulation of Type II fatty acid synthesis. Biochem Soc Trans 30: 1050–1055. doi:10.1042/BST0301050

    Article  PubMed  CAS  Google Scholar 

  7. Rock CO, Cronan JE (1996) Escherichia coli as a model for the regulation of dissociable (type II) fatty acid biosynthesis. Biochim Biophys Acta 1302: 1–16

    PubMed  Google Scholar 

  8. Jacobsson M, Garedal M, Schultz J, Karlen A (2008) Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening. J Med Chem 51: 2777–2786. doi:10.1021/jm7016144

    Article  PubMed  CAS  Google Scholar 

  9. Nicola G, Smith CA, Lucumi E, Kuo MR, Karagyozov L, Fidock DA, Sacchettini JC, Abagyan R (2007) Discovery of novel inhibitors targeting enoyl-acyl carrier protein reductase in Plasmodium falciparum by structure-based virtual screening. Biochem Biophys Res Commun 358: 686–691. doi:10.1016/j.bbrc.2007.04.113

    Article  PubMed  CAS  Google Scholar 

  10. Campbell JW, Cronan JE Jr (2001) Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery. Annu Rev Microbiol 55: 305–332. doi:10.1146/annurev.micro.55.1.305

    Article  PubMed  CAS  Google Scholar 

  11. Perozzo R, Kuo M, Sidhu AS, Valiyaveettil JT, Bittman R, Jacobs WR Jr, Fidock DA, Sacchettini JC (2002) Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase. J Biol Chem 277: 13106–13114. doi:10.1074/jbc.M112000200

    Article  PubMed  CAS  Google Scholar 

  12. Sybyl 7.1, Tripos Inc., St. Louis, Missouri, USA

  13. Cramer RD, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110: 5959–5967. doi:10.1021/ja00226a005

    Article  CAS  Google Scholar 

  14. Cramer RD 3rd, Patterson DE, Bunce JD (1989) Recent advances in comparative molecular field analysis (CoMFA). Prog Clin Biol Res 291: 161–165

    Google Scholar 

  15. Bohm M, Strzebecher J, Klebe G (1999) Three-dimensional quantitative structure–activity relationship analyses using comparative molecular field analysis and comparative molecular similarity indices analysis to elucidate selectivity differences of inhibitors binding to trypsin, thrombin, and factor Xa. J Med Chem 42: 458–477. doi:10.1021/jm981062r

    Article  PubMed  CAS  Google Scholar 

  16. Klebe G (1998) Comparative molecular similarity indices analysis: CoMSIA. Perspect Drug Discov Des 12: 87–104. doi:0.1023/A:1017025803403

    Article  Google Scholar 

  17. Klebe G, Abraham U, Mietzner T (1994) Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. J Med Chem 37: 4130–4146. doi:10.1021/jm00050a010

    Article  PubMed  CAS  Google Scholar 

  18. Gold 3.2, CCDC, Cambridge, UK

  19. iResearch database, ChemNavigator, Inc., San Diego, CA, USA

  20. Verdonk M, Cole J, Hartshorn M, Murray C, Taylor R (2003) Improved protein–ligand docking using GOLD. Proteins 52: 609–623. doi:10.1002/prot.10465

    Article  PubMed  CAS  Google Scholar 

  21. Eldridge MD, Murray CW, Auton TR, Paolini GV, Mee RP (1997) Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J Comput Aided Mol Des 11: 425–445. doi:10.1023/A:1007996124545

    CAS  Google Scholar 

  22. Mooij WT, Verdonk ML (2005) General and targeted statistical potentials for protein–ligand interactions. Proteins Struct Funct Bioinform 61: 272–287. doi:10.1002/prot.20588

    Article  CAS  Google Scholar 

  23. Krammer A, Kirchhoff PD, Jiang X, Venkatachalam CM, Waldman M (2005) LigScore: a novel scoring function for predicting binding affinities. J Mol Graph Model 23: 395–407. doi:10.1016/j.jmgm.2004.11.007

    Article  PubMed  CAS  Google Scholar 

  24. Gehlhaar DK, Verkhivker GM, Rejto PA, Sherman CJ, Fogel DB, Fogel LJ, Freer ST (1995) Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming. Chem Biol 2: 317–324. doi:10.1016/1074-5521(95)90050-0

    Article  PubMed  CAS  Google Scholar 

  25. Jain AN (1996) Scoring noncovalent protein–ligand interactions: a continuous differentiable function tuned to compute binding affinities. J Comput Aided Mol Des 10: 427–440. doi:10.1007/BF00124474

    Article  PubMed  CAS  Google Scholar 

  26. Muegge I, Martin YC (1999) A general and fast scoring function for protein–ligand interactions: a simplified potential approach. J Med Chem 42: 791–804. doi:10.1021/jm980536j

    Article  PubMed  CAS  Google Scholar 

  27. Bohm HJ (1994) The development of a simple empirical scoring function to estimate the binding constant for a protein–ligand complex of known three-dimensional structure. J Comput Aided Mol Des 8: 243–256. doi:10.1007/BF00126743

    Article  PubMed  CAS  Google Scholar 

  28. Cerius2 XI, Accelrys Inc., San Diego, California, USA, XI

  29. Chhibber M, Kumar G, Parasuraman P, Ramya TN, Surolia N, Surolia A (2006) Novel diphenyl ethers: design, docking studies, synthesis and inhibition of enoyl ACP reductase of Plasmodium falciparum and Escherichia coli. Bioorg Med Chem 14: 8086–8098. doi:10.1016/j.bmc.2006.07.034

    Article  PubMed  CAS  Google Scholar 

  30. Freundlich JS, Anderson JW, Sarantakis D, Shieh HM, Yu M, Valderramos JC, Lucumi E, Kuo M, Jacobs WR Jr, Fidock DA, Schiehser GA, Jacobus DP, Sacchettini JC (2005) Synthesis, biological activity, and X-ray crystal structural analysis of diaryl ether inhibitors of malarial enoyl acyl carrier protein reductase. Part 1: 4′-substituted triclosan derivatives. Bioorg Med Chem Lett 15:5247–5252. doi:10.1016/j.bmcl.2005.08.044

    Google Scholar 

  31. Freundlich JS, Yu M, Lucumi E, Kuo M, Tsai HC, Valderramos JC, Karagyozov L, Jacobs WR Jr, Schiehser GA, Fidock DA, Jacobus DP, Sacchettini JC (2006) Synthesis and biological activity of diaryl ether inhibitors of malarial enoyl acyl carrier protein reductase. Part 2: 2′-substituted triclosan derivatives. Bioorg Med Chem Lett 16:2163–2169. doi:10.1016/j.bmcl.2006.01.051

    Google Scholar 

  32. Nayyar A, Malde A, Jain R, Coutinho E (2006) 3D-QSAR study of ring-substituted quinoline class of anti-tuberculosis agents. Bioorg Med Chem 14: 847–856. doi:10.1016/j.bmc.2005.09.018

    Article  PubMed  CAS  Google Scholar 

  33. Pissurlenkar RR, Shaikh MS, Coutinho EC (2007) 3D-QSAR studies of dipeptidyl peptidase IV inhibitors using a docking based alignment. J Mol Model 13: 1047–1071. doi:10.1007/s00894-007-0227-2

    Article  PubMed  CAS  Google Scholar 

  34. Virsodia V, Pissurlenkar RR, Manvar D, Dholakia C, Adlakha P, Shah A, Coutinho EC (2008) Synthesis, screening for antitubercular activity and 3D-QSAR studies of substituted N-phenyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxamides. Eur J Med Chem 43: 2103–2115. doi:10.1016/j.ejmech.2007.08.004

    Article  PubMed  CAS  Google Scholar 

  35. Tanimoto TT (1961) Non-linear model for a computer assisted medical diagnostic procedure. Trans N Y Acad Sci 23: 576–578

    Google Scholar 

  36. Datar PA, Coutinho EC (2004) A CoMFA study of COX-2 inhibitors with receptor based alignment. J Mol Graph Model 23: 239–251. doi:10.1016/j.jmgm.2004.07.003

    Article  PubMed  CAS  Google Scholar 

  37. Wold S, Johansson E, Cocchi M (1993) PLS-partial least squares projections to latent structures in 3D-QSAR. ESCOM Lieden: The Netherlands

  38. Bush BL, Nachbar RB Jr (1993) Sample-distance partial least squares: PLS optimized for many variables, with application to CoMFA. J Comput Aided Mol Des 7: 587–619. doi:10.1007/BF00124364

    Article  PubMed  CAS  Google Scholar 

  39. Legar C, Romano JP, Politis DN (1992) Bootstrap technology and applications. Technometrics 34: 378–398. doi:10.2307/1268938

    Article  Google Scholar 

  40. Judefind WL, Reid EE (1920) The identification of acids. V. Para halogen phenacyl esters. J Am Chem Soc 42: 1043–1055. doi:10.1021/ja01450a019

    Article  CAS  Google Scholar 

  41. Dodson RM, King LC (1945) The reaction of ketones with halogens and thiourea. J Am Chem Soc 67: 2242–2243. doi:10.1021/ja01228a059

    Article  CAS  Google Scholar 

  42. Erian AW, Sherif SM, Gaber HM (2003) The chemistry of α-haloketones and their utility in heterocyclic synthesis. Molecules 8: 793–865. doi:10.3390/81100793

    Article  CAS  Google Scholar 

  43. Furness BS, Hannaford AJ, Smith PW, Tatchell AR (1994) Vogel’s textbook of practical organic chemistry, 5th edn. Longman Scientific & Technical, Essex, UK

    Google Scholar 

  44. Zav’yalov SI, Dorofeeva OV, Rumyantseva EE, Kulikova LB, Ezhova GI, Kravchenko NE, Zavozin AG (2001) Synthesis of 2-aminothiazole derivatives. Pharm Chem J 35: 96–98. doi:10.1023/A:1010477022450

    Article  Google Scholar 

  45. Kalra B, Chawla S, Gupta P, Valecha N (2006) Screening of antimalarial drugs: an overview. Indian J Pharmacol 38: 5–12

    Article  CAS  Google Scholar 

  46. Pidugu LS, Kapoor M, Surolia N, Surolia A, Suguna K (2004) Structural basis for the variation in triclosan affinity to enoyl reductases. J Mol Biol 343: 147–155. doi:10.1016/j.jmb.2004.08.033

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, 400 098, India

    Varun A. Morde, Mushtaque S. Shaikh, Raghuvir R. S. Pissurlenkar & Evans C. Coutinho

Authors
  1. Varun A. Morde
    View author publications

    Search author on:PubMed Google Scholar

  2. Mushtaque S. Shaikh
    View author publications

    Search author on:PubMed Google Scholar

  3. Raghuvir R. S. Pissurlenkar
    View author publications

    Search author on:PubMed Google Scholar

  4. Evans C. Coutinho
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Evans C. Coutinho.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morde, V.A., Shaikh, M.S., Pissurlenkar, R.R.S. et al. Molecular modeling studies, synthesis, and biological evaluation of Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR) inhibitors. Mol Divers 13, 501–517 (2009). https://doi.org/10.1007/s11030-009-9141-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-009-9141-0

Keywords

Profiles

  1. Raghuvir R. S. Pissurlenkar View author profile