Journal of Computer-Aided Molecular Design

, Volume 29, Issue 1, pp 79–87 | Cite as

In silico screening for Plasmodium falciparum enoyl-ACP reductase inhibitors

  • Steffen Lindert
  • Lorillee Tallorin
  • Quynh G. Nguyen
  • Michael D. Burkart
  • J. Andrew McCammon
Article

Abstract

The need for novel therapeutics against Plasmodium falciparum is urgent due to recent emergence of multi-drug resistant malaria parasites. Since fatty acids are essential for both the liver and blood stages of the malarial parasite, targeting fatty acid biosynthesis is a promising strategy for combatting P. falciparum. We present a combined computational and experimental study to identify novel inhibitors of enoyl-acyl carrier protein reductase (PfENR) in the fatty acid biosynthesis pathway. A small-molecule database from ChemBridge was docked into three distinct PfENR crystal structures that provide multiple receptor conformations. Two different docking algorithms were used to generate a consensus score in order to rank possible small molecule hits. Our studies led to the identification of five low-micromolar pyrimidine dione inhibitors of PfENR.

Keywords

Computer-aided drug discovery Enoyl-acyl carrier protein reductase Virtual screening 

Supplementary material

10822_2014_9806_MOESM1_ESM.docx (2 mb)
Supplementary material 1 (DOCX 2057 kb)

References

  1. 1.
    Bourzac K (2014) Infectious disease: beating the big three. Nature 507:S4–S7CrossRefGoogle Scholar
  2. 2.
    Rich SM, Leendertz FH, Xu G, LeBreton M, Djoko CF, Aminake MN, Takang EE, Diffo JL, Pike BL, Rosenthal BM, Formenty P, Boesch C, Ayala FJ, Wolfe ND (2009) The origin of malignant malaria. Proc Natl Acad Sci USA 106:14902–14907CrossRefGoogle Scholar
  3. 3.
    Tschan S, Kremsner PG, Mordmuller B (2012) Emerging drugs for malaria. Expert Opin Emerg Drugs 17:319–333CrossRefGoogle Scholar
  4. 4.
    O’Brien C, Henrich PP, Passi N, Fidock DA (2011) Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum. Curr Opin Infect Dis 24:570–577CrossRefGoogle Scholar
  5. 5.
    Nayyar GM, Breman JG, Newton PN, Herrington J (2012) Poor-quality antimalarial drugs in southeast Asia and sub-Saharan Africa. Lancet Infect Dis 12:488–496CrossRefGoogle Scholar
  6. 6.
    Klonis N, Crespo-Ortiz MP, Bottova I, Abu-Bakar N, Kenny S, Rosenthal PJ, Tilley L (2011) Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion. Proc Natl Acad Sci USA 108:11405–11410CrossRefGoogle Scholar
  7. 7.
    Schrader FC, Glinca S, Sattler JM, Dahse HM, Afanador GA, Prigge ST, Lanzer M, Mueller AK, Klebe G, Schlitzer M (2013) Novel type II fatty acid biosynthesis (FAS II) inhibitors as multistage antimalarial agents. ChemMedChem 8:442–461CrossRefGoogle Scholar
  8. 8.
    Elabbadi N, Ancelin ML, Vial HJ (1992) Use of radioactive ethanolamine incorporation into phospholipids to assess invitro antimalarial activity by the semiautomated microdilution technique. Antimicrob Agents Chemother 36:50–55CrossRefGoogle Scholar
  9. 9.
    Vial HJ, Thuet MJ, Philippot JR (1982) Phospholipid biosynthesis in synchronous Plasmodium falciparum cultures. J Protozool 29:258–263CrossRefGoogle Scholar
  10. 10.
    Ralph SA, van Dooren GG, Waller RF, Crawford MJ, Fraunholz MJ, Foth BJ, Tonkin CJ, Roos DS, McFadden GI (2004) Tropical infectious diseases: metabolic maps and functions of the Plasmodium falciparum apicoplast. Nat Rev Microbiol 2:203–216CrossRefGoogle Scholar
  11. 11.
    Waller RF, Keeling PJ, Donald RG, Striepen B, Handman E, Lang-Unnasch N, Cowman AF, Besra GS, Roos DS, McFadden GI (1998) Nuclear-encoded proteins target to the plastid in Toxoplasma gondii and Plasmodium falciparum. Proc Natl Acad Sci USA 95:12352–12357CrossRefGoogle Scholar
  12. 12.
    Yu M, Kumar TR, Nkrumah LJ, Coppi A, Retzlaff S, Li CD et al (2008) The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites. Cell Host Microbe 4:567–578CrossRefGoogle Scholar
  13. 13.
    Qidwai T, Khan F (2012) Antimalarial drugs and drug targets specific to fatty acid metabolic pathway of Plasmodium falciparum. Chem Biol Drug Des 80:155–172CrossRefGoogle Scholar
  14. 14.
    Vaughan AM, O’Neill MT, Tarun AS, Camargo N, Phuong TM, Aly AS, Cowman AF, Kappe SH (2009) Type II fatty acid synthesis is essential only for malaria parasite late liver stage development. Cell Microbiol 11:506–520CrossRefGoogle Scholar
  15. 15.
    Derbyshire ER, Mota MM, Clardy J (2011) The next opportunity in anti-malaria drug discovery: the liver stage. PLoS Pathog 7:e1002178CrossRefGoogle Scholar
  16. 16.
    Mazier D, Renia L, Snounou G (2009) A pre-emptive strike against malaria’s stealthy hepatic forms. Nat Rev Drug Discov 8:854–864CrossRefGoogle Scholar
  17. 17.
    Roujeinikova A, Sedelnikova S, de Boer GJ, Stuitje AR, Slabas AR, Rafferty JB, Rice DW (1999) Inhibitor binding studies on enoyl reductase reveal conformational changes related to substrate recognition. J Biol Chem 274:30811–30817CrossRefGoogle Scholar
  18. 18.
    Heath RJ, Yu YT, Shapiro MA, Olson E, Rock CO (1998) Broad spectrum antimicrobial biocides target the FabI component of fatty acid synthesis. J Biol Chem 273:30316–30320CrossRefGoogle Scholar
  19. 19.
    Hayashi T, Yamamoto O, Sasaki H, Kawaguchi A, Okazaki H (1983) Mechanism of action of the antibiotic thiolactomycin inhibition of fatty acid synthesis of Escherichia coli. Biochem Biophys Res Commun 115:1108–1113CrossRefGoogle Scholar
  20. 20.
    Jackowski S, Murphy CM, Cronan JE Jr, Rock CO (1989) Acetoacetyl-acyl carrier protein synthase. A target for the antibiotic thiolactomycin. J Biol Chem 264:7624–7629Google Scholar
  21. 21.
    Nishida I, Kawaguchi A, Yamada M (1986) Effect of thiolactomycin on the individual enzymes of the fatty acid synthase system in Escherichia coli. J Biochem 99:1447–1454Google Scholar
  22. 22.
    Baldock C, Rafferty JB, Sedelnikova SE, Baker PJ, Stuitje AR, Slabas AR, Hawkes TR, Rice DW (1996) A mechanism of drug action revealed by structural studies of enoyl reductase. Science 274:2107–2110CrossRefGoogle Scholar
  23. 23.
    Parikh SL, Xiao G, Tonge PJ (2000) Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid. Biochemistry 39:7645–7650CrossRefGoogle Scholar
  24. 24.
    Freundlich JS, Wang F, Tsai HC, Kuo M, Shieh HM, Anderson JW et al (2007) X-ray structural analysis of Plasmodium falciparum enoyl acyl carrier protein reductase as a pathway toward the optimization of triclosan antimalarial efficacy. J Biol Chem 282:25436–25444CrossRefGoogle Scholar
  25. 25.
    Kumar G, Parasuraman P, Sharma SK, Banerjee T, Karmodiya K, Surolia N, Surolia A (2007) Discovery of a rhodanine class of compounds as inhibitors of Plasmodium falciparum enoyl-acyl carrier protein reductase. J Med Chem 50:2665–2675CrossRefGoogle Scholar
  26. 26.
    McLeod R, Muench SP, Rafferty JB, Kyle DE, Mui EJ, Kirisits MJ, Mack DG, Roberts CW, Samuel BU, Lyons RE, Dorris M, Milhous WK, Rice DW (2001) Triclosan inhibits the growth of Plasmodium falciparum and Toxoplasma gondii by inhibition of apicomplexan Fab I. Int J Parasitol 31:109–113CrossRefGoogle Scholar
  27. 27.
    Tallorin L, Durrant JD, Nguyen QG, McCammon JA, Burkart MD (2014) Celastrol inhibits Plasmodium falciparum enoyl-acyl carrier protein reductase. Biorgan Med Chem. doi:10.1016/j.bmc.2014.09.002
  28. 28.
    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 343:147–155CrossRefGoogle Scholar
  29. 29.
    Ward WH, Holdgate GA, Rowsell S, McLean EG, Pauptit RA, Clayton E et al (1999) Kinetic and structural characteristics of the inhibition of enoyl (acyl carrier protein) reductase by triclosan. Biochemistry 38:12514–12525CrossRefGoogle Scholar
  30. 30.
    Oliveira JS, Vasconcelos IB, Moreira IS, Santos DS, Basso LA (2007) Enoyl reductases as targets for the development of anti-tubercular and anti-malarial agents. Curr Drug Targets 8:399–411CrossRefGoogle Scholar
  31. 31.
    Belluti F, Perozzo R, Lauciello L, Colizzi F, Kostrewa D, Bisi A, Gobbi S, Rampa A, Bolognesi ML, Recanatini M, Brun R, Scapozza L, Cavalli A (2013) Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI). J Med Chem 56:7516–7526CrossRefGoogle Scholar
  32. 32.
    Lu X, Huang K, You Q (2011) Enoyl acyl carrier protein reductase inhibitors: a patent review (2006–2010). Expert Opin Ther Pat 21:1007–1022CrossRefGoogle Scholar
  33. 33.
    Maity K, Bhargav SP, Sankaran B, Surolia N, Surolia A, Suguna K (2010) X-ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibition. IUBMB Life 62:467–476Google Scholar
  34. 34.
    Andricopulo AD, Salum LB, Abraham DJ (2009) Structure-based drug design strategies in medicinal chemistry. Curr Top Med Chem 9:771–790CrossRefGoogle Scholar
  35. 35.
    Lee HM, Singh NJ (2011) Understanding drug–protein interactions in Escherichia coli FabI and various fabi inhibitor complexes. B Korean Chem Soc 32:162–168CrossRefGoogle Scholar
  36. 36.
    Pasqualoto KFM, Ferreira MMC (2006) Application of a receptor pruning methodology to the enoyl-ACP reductase from Escherichia coli (Fabl). QSAR Comb Sci 25:629–636CrossRefGoogle Scholar
  37. 37.
    Singh NJ, Shin D, Lee HM, Kim HT, Chang HJ, Cho JM, Kim KS, Ro S (2011) Structural basis of triclosan resistance. J Struct Biol 174:173–179CrossRefGoogle Scholar
  38. 38.
    Yang L, Liu Y, Sternberg C, Molin S (2010) Evaluation of enoyl-acyl carrier protein reductase inhibitors as Pseudomonas aeruginosa quorum-quenching reagents. Molecules 15:780–792CrossRefGoogle Scholar
  39. 39.
    Lindert S, McCammon JA (2012) Dynamics of Plasmodium falciparum enoyl-ACP reductase and implications on drug discovery. Protein Sci 21:1734–1745CrossRefGoogle Scholar
  40. 40.
    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 358:686–691CrossRefGoogle Scholar
  41. 41.
    Morde VA, Shaikh MS, Pissurlenkar RR, Coutinho EC (2009) Molecular modeling studies, synthesis, and biological evaluation of Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR) inhibitors. Mol Divers 13:501–517CrossRefGoogle Scholar
  42. 42.
    Frecer V, Megnassan E, Miertus S (2009) Design and in silico screening of combinatorial library of antimalarial analogs of triclosan inhibiting Plasmodium falciparum enoyl-acyl carrier protein reductase. Eur J Med Chem 44:3009–3019CrossRefGoogle Scholar
  43. 43.
    Shah P, Siddiqi MI (2010) 3D-QSAR studies on triclosan derivatives as Plasmodium falciparum enoyl acyl carrier reductase inhibitors. SAR QSAR Environ Res 21:527–545CrossRefGoogle Scholar
  44. 44.
    Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22:195–201CrossRefGoogle Scholar
  45. 45.
    Dolinsky TJ, Czodrowski P, Li H, Nielsen JE, Jensen JH, Klebe G, Baker NA (2007) PDB2PQR: expanding and upgrading automated preparation of biomolecular structures for molecular simulations. Nucleic Acids Res 35:W522–W525CrossRefGoogle Scholar
  46. 46.
    Dolinsky TJ, Nielsen JE, McCammon JA, Baker NA (2004) PDB2PQR: an automated pipeline for the setup of Poisson–Boltzmann electrostatics calculations. Nucleic Acids Res 32:W665–W667CrossRefGoogle Scholar
  47. 47.
    Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791CrossRefGoogle Scholar
  48. 48.
    Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27:221–234CrossRefGoogle Scholar
  49. 49.
    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 47:1739–1749CrossRefGoogle Scholar
  50. 50.
    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 47:1750–1759CrossRefGoogle Scholar
  51. 51.
    Lee HS, Choi J, Kufareva I, Abagyan R, Filikov A, Yang Y, Yoon S (2008) Optimization of high throughput virtual screening by combining shape-matching and docking methods. J Chem Inf Model 48:489–497CrossRefGoogle Scholar
  52. 52.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26CrossRefGoogle Scholar
  53. 53.
    Trott O, Olson AJ (2009) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461Google Scholar
  54. 54.
    Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 49:6177–6196CrossRefGoogle Scholar
  55. 55.
    Lindert S, Zhu W, Liu YL, Pang R, Oldfield E, McCammon JA (2013) Farnesyl diphosphate synthase inhibitors from in silico screening. Chem Biol Drug Des 81(6):742–748Google Scholar
  56. 56.
    Duan J, Dixon SL, Lowrie JF, Sherman W (2010) Analysis and comparison of 2D fingerprints: insights into database screening performance using eight fingerprint methods. J Mol Graph Model 29:157–170CrossRefGoogle Scholar
  57. 57.
    Sastry M, Lowrie JF, Dixon SL, Sherman W (2010) Large-scale systematic analysis of 2D fingerprint methods and parameters to improve virtual screening enrichments. J Chem Inf Model 50:771–784CrossRefGoogle Scholar
  58. 58.
    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 277:13106–13114CrossRefGoogle Scholar
  59. 59.
    Choi KH, Kremer L, Besra GS, Rock CO (2000) Identification and substrate specificity of beta-ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis. J Biol Chem 275:28201–28207Google Scholar
  60. 60.
    Surolia N, Surolia A (2001) Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum. Nat Med 7:167–173CrossRefGoogle Scholar
  61. 61.
    Kapoor M, Gopalakrishnapai J, Surolia N, Surolia A (2004) Mutational analysis of the triclosan-binding region of enoyl-ACP (acyl-carrier protein) reductase from Plasmodium falciparum. Biochem J 381:735–741CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Steffen Lindert
    • 1
    • 2
    • 3
  • Lorillee Tallorin
    • 3
  • Quynh G. Nguyen
    • 3
  • Michael D. Burkart
    • 3
  • J. Andrew McCammon
    • 1
    • 2
    • 3
    • 4
    • 5
  1. 1.Department of PharmacologyUniversity of California San DiegoLa JollaUSA
  2. 2.Center for Theoretical Biological PhysicsLa JollaUSA
  3. 3.Department of Chemistry and BiochemistryUniversity of California San DiegoLa JollaUSA
  4. 4.Howard Hughes Medical InstituteUniversity of California San DiegoLa JollaUSA
  5. 5.National Biomedical Computation ResourceUniversity of California San DiegoLa JollaUSA

Personalised recommendations