European Biophysics Journal

, Volume 46, Issue 5, pp 445–459 | Cite as

Investigation of the binding mode of 1, 3, 4-oxadiazole derivatives as amide-based inhibitors for soluble epoxide hydrolase (sEH) by molecular docking and MM-GBSA

  • Leila Karami
  • Ali Akbar Saboury
  • Elham Rezaee
  • Sayyed Abbas Tabatabai
Original Article

Abstract

The soluble epoxide hydrolase (sEH) enzyme plays an important role in the metabolism of endogenous chemical mediators involved in the regulation of blood pressure and inflammation. Inhibition of sEH provides a new approach to the treatment of inflammation, hypertension and atherosclerosis. In this study, the binding modes and inhibition mechanisms of the new oxadiazole-based amide inhibitors of the human soluble epoxide hydrolase were investigated by molecular docking and molecular dynamics (MD) simulation followed by the MM-GBSA method to calculate the binding free energy of each inhibitor to sEH. The results obtained from the binding free energy (ΔGbinding) calculation and normal mode analysis indicate that the major favorable contributors are the van der Waals and electrostatic terms, whereas the polar solvation term opposes binding. In addition, a good agreement between the calculated ΔGbinding and the experimental IC50 was obtained [correlation coefficient, r2 = 0.89 (with) and 0.87 (without) entropy]. Besides, comparison of the enthalpy changes (ΔGMM-GBSA) with entropy changes (–TΔS) indicates that binding process of all inhibitors to sEH is enthalpy-driven. Based on the ΔGbinding on per residue decomposition, Asp335 and Tyr383 residues from the active site and Trp336, Leu499 and His524 residues from hydrophobic pockets contribute the most to ΔGbinding. Moreover, hydrogen bond analysis reveals that Tyr383, Tyr466 and Asp335 residues have an important role in the binding to inhibitors by forming hydrogen bonds with high occupancies. Our obtained results are useful for the understanding of the sEH-inhibitor interactions and may have great importance in the design of future sEH inhibitors.

Keywords

Soluble epoxide hydrolase Blood pressure Inflammation Molecular docking Molecular dynamics simulation MM-GBSA 

References

  1. Anandan SK, Gless RD (2010) Exploration of secondary and tertiary pharmacophores in unsymmetrical N, N’-diaryl urea inhibitors of soluble epoxide hydrolase. Bioorg Med Chem Lett 20:2740–2744. doi:10.1016/j.bmcl.2010.03.074 CrossRefPubMedGoogle Scholar
  2. Anandan SK, Do ZN, Webb HK, Patel DV, Gless RD (2009) Non-urea functionality as the primary pharmacophore in soluble epoxide hydrolase inhibitors. Bioorg Med Chem Lett 19:1066–1070. doi:10.1016/j.bmcl.2009.01.013 CrossRefPubMedGoogle Scholar
  3. Åqvist J, Medina C, Samuelsson J-E (1994) A new method for predicting binding affinity in computer-aided drug design. Protein Eng 7:385–391. doi:10.1093/protein/7.3.385 CrossRefPubMedGoogle Scholar
  4. Arand M, Cronin A, Adamska M, Oesch F (2005) Epoxide hydrolases: structure, function, mechanism, and assay. Method Enzymol 400:569–588. doi:10.1016/s0076-6879(05)00032-7 CrossRefGoogle Scholar
  5. Argiriadi MA, Morisseau C, Hammock BD, Christianson DW (1999) Detoxification of environmental mutagens and carcinogens: structure, mechanism, and evolution of liver epoxide hydrolase. P Natl Acad Sci USA 96:10637–10642. doi:10.1073/pnas.96.19.10637 CrossRefGoogle Scholar
  6. Beveridge DL, DiCapua FM (1989) Free energy via molecular simulation: applications to chemical and biomolecular systems. Ann Rev Biophys Bio 8:431–492. doi:10.1146/annurev.bb.18.060189.002243 CrossRefGoogle Scholar
  7. Borhan B, Jones AD, Pinot F, Grant DF, Kurth MJ, Hammock BD (1995) mechanism of soluble epoxide hydrolase: formation of an -hydroxy ester–enzyme intermediate through ASP-333. J Biol Chem 270:26923–26930. doi:10.1074/jbc.270.45.26923 CrossRefPubMedGoogle Scholar
  8. Connolly ML (1983) Analytical molecular surface calculation. J Appl Crystallogr 16:548–558. doi:10.1107/s0021889883010985 CrossRefGoogle Scholar
  9. Cronin A, Homburg S, Durk H, Richter I, Adamska M, Frere F, Arand M (2008) Insights into the catalytic mechanism of human sEH phosphatase by site-directed mutagenesis and LC-MS/MS analysis. J Mol Biol 383:627–640. doi:10.1016/j.jmb.2008.08.049 CrossRefPubMedGoogle Scholar
  10. Davis BB, Thompson DA, Howard LL, Morisseau C, Hammock BD, Weiss RH (2002) Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation. P Natl Acad Sci USA 99:2222–2227. doi:10.1073/pnas.261710799 CrossRefGoogle Scholar
  11. Dietze EC, Kuwano E, Casas J, Hammock BD (1991) Inhibition of cytosolic epoxide hydrolase by trans-3-phenylglycidols. Biochem Pharmacol 42:1163–1175. doi:10.1016/0006-2952(91)90250-9 CrossRefPubMedGoogle Scholar
  12. Duan Y, Wu C, Chowdhury S et al (2003) A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput Chem 24:1999–2012. doi:10.1002/jcc.10349 CrossRefPubMedGoogle Scholar
  13. Eldrup AB, Soleymanzadeh F, Taylor SJ et al (2009) Structure-based optimization of arylamides as inhibitors of soluble epoxide hydrolase. J Med Chem 52:5880–5895. doi:10.1021/jm9005302 CrossRefPubMedGoogle Scholar
  14. Eldrup AB, Soleymanzadeh F, Farrow NA, Kukulka A, De Lombaert S (2010) Optimization of piperidyl-ureas as inhibitors of soluble epoxide hydrolase. Bioorg Med Chem Lett 20:571–575. doi:10.1016/j.bmcl.2009.11.091 CrossRefPubMedGoogle Scholar
  15. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593. doi:10.1063/1.470117 CrossRefGoogle Scholar
  16. Fretland AJ, Omiecinski CJ (2000) Epoxide hydrolases: biochemistry and molecular biology. Chem-Biol Interact 129:41–59. doi:10.1016/s0009-2797(00)00197-6 CrossRefPubMedGoogle Scholar
  17. Frisch MJ, Trucks GW, Schlegel HB et al (2004) Gaussian03, revision C.02. Gaussian Inc., Wallingford CTGoogle Scholar
  18. Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron 36:3219–3228. doi:10.1016/0040-4020(80)80168-2 CrossRefGoogle Scholar
  19. Gomez GA, Moriseau C, Hammock BD, Christianson DW (2006) Human soluble epoxide Hydrolase: structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids. Protein Sci 15:58–64. doi:10.1110/ps.051720206 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Hou T, Wang J, Li Y, Wang W (2011) Assessing the performance of the MM/PBSA and MM/GBSA methods: I. the accuracy of binding free energy calculations based on molecular dynamics simulations. J Chem Inf Model 51:69–82. doi:10.1021/ci1000275a CrossRefPubMedGoogle Scholar
  21. Huang SX, Cao B, Morisseau C, Jin Y, Hammock BD, Long YQ (2012) Structure-based optimization of the piperazino-containing 1,3-disubstituted ureas affording sub-nanomolar inhibitors of soluble epoxide hydrolase. Med Chem Comm 3:379–384. doi:10.1039/C2MD00288D CrossRefGoogle Scholar
  22. Imig JD, Hammock BD (2009) Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nat Rev Drug Discov 8:794–805. doi:10.1038/nrd2875 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Imig JD, Zhao X, Capdevila JH, Morisseau C, Hammock BD (2002) Soluble epoxide hydrolase inhibition lowers arterial blood pressure in angiotensin II hypertension. Hypertension 39:690–694. doi:10.1161/hy0202.103788 CrossRefPubMedGoogle Scholar
  24. Imig JD, Carpenter MA, Shaw S (2009) The soluble epoxide hydrolase inhibitor AR9281 decreases blood pressure, ameliorates renal injury and improves vascular function in hypertension. Pharmaceuticals 2:217–227. doi:10.3390/ph2030217 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Ingraham RH, Gless RD, Lo HY (2011) Soluble epoxide hydrolase inhibitors and their potential for treatment of multiple pathologic conditions. Curr Med Chem 18:587–603. doi:10.2174/092986711794480212 CrossRefPubMedGoogle Scholar
  26. Jakalian A, Jack DB, Bayly CI (2002) Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation. J Comput Chem 23:1623–1641. doi:10.1002/jcc.10128 CrossRefPubMedGoogle Scholar
  27. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926. doi:10.1063/1.445869 CrossRefGoogle Scholar
  28. Karplus M, MacCammon JA (2002) Molecular dynamis simulations of biomolecules. Nat Struct Biol 9:646–652. doi:10.1038/nsb0902-646 CrossRefPubMedGoogle Scholar
  29. Kim IH, Heirtzler FR, Morisseau C, Nishi K, Tsai HJ, Hammock BD (2005) Optimization of amide-based inhibitors of soluble epoxide hydrolase with improved water solubility. J Med Chem 48:3621–3629. doi:10.1021/jm0500929 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kim IH, Nishi K, Tsai HJ et al (2007) Design of bioavailable derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a potent inhibitor of the soluble epoxide hydrolase. Bioorg Med Chem 15:312–323. doi:10.1016/j.bmc.2006.09.057 CrossRefPubMedGoogle Scholar
  31. Kim IH, Park YK, Hammock BD, Nishi K (2011) Structure-activity relationships of cycloalkylamide derivatives as inhibitors of the soluble epoxide hydrolase. J Med Chem 54:1752–1761. doi:10.1021/jm101431v CrossRefPubMedPubMedCentralGoogle Scholar
  32. Kim IH, Nishi K, Kasagami T, Morisseau C, Liu JY, Tsai HJ, Hammock BD (2012) Biologically active ester derivatives as potent inhibitors of the soluble epoxide hydrolase. Bioorg Med Chem Lett 22:5889–5892. doi:10.1016/j.bmcl.2012.07.074 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Kirkwood JG (1935) Statistical mechanics of fluid mixtures. J Chem Phys 3:300–313. doi:10.1063/1.1749657 CrossRefGoogle Scholar
  34. Kollman P (1993) Free energy calculations: applications to chemical and biochemical phenomena. Chem Rev 93:2395–2417. doi:10.1021/cr00023a004 CrossRefGoogle Scholar
  35. Kollman PA, Massova I, Reyes C et al (2000) Calculating structures and free energies of complex molecules: Combining molecular mechanics and continuum models. Accounts Chem Res 33:889–897. doi:10.1021/ar000033j CrossRefGoogle Scholar
  36. Krepl M, Clery A, Blatter M, Allain FHT, Sponer J (2016) Synergy between NMR measurments and MD simulations of protein/RNA complexes: application to the RRMs, the most common RNA recognition motifs. Nucleic Acids Res. doi:10.1093/nar/gkw438 PubMedPubMedCentralGoogle Scholar
  37. Massova I, Kollman PA (2000) Combined molecular mechanical and continuum solvent approach (MM-PBSA/GBSA) to predict ligand binding. Perspect Drug Discov 18:113–135. doi:10.1023/a:1008763014207 CrossRefGoogle Scholar
  38. Miller BR, McGee TD Jr, Swaile JM, Homeyer N, Gohlke H, Roitberg AE (2012) MMPBSA.py: an efficient program for end-state free energy calculation. J Chem Theory Comput 8:3314–3321. doi:10.1021/dt300418h CrossRefPubMedGoogle Scholar
  39. Miyamoto T, Silva M, Hammock BD (1987) Inhibition of epoxide hydrolases and glutathione S-transferases by 2-, 3-, and 4-substituted derivatives of 4′-phenylchalcone and its oxide. Arch Biochem Biophys 254:203–213. doi:10.1016/0003-9861(87)90096-8 CrossRefPubMedGoogle Scholar
  40. 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 30:2785–2791. doi:10.1002/jcc.21256 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Newman JW, Morisseau C, Hammock BD (2005) Epoxide hydrolases: their roles and interactions with lipid metabolism. Prog Lipid Res 44:1–51. doi:10.1016/j.plipres.2004.10.001 CrossRefPubMedGoogle Scholar
  42. Onufriev A, Bashford D, Case DA (2000) Modification of the generalized born model Suitable for macromolecules. J Phys Chem B 104:3712–3720. doi:10.1021/jp994072s CrossRefGoogle Scholar
  43. Pearlman DA, Case DA, Caldwell JW et al (1995) AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules. Comput Phys Commun 91:1–41. doi:10.1016/0010-4655(95)00041-d CrossRefGoogle Scholar
  44. Pecic S, Deng SX, Morisseau C, Hammock BD, Landry DW (2012) Design, synthesis and evaluation of non-urea inhibitors of soluble epoxide hydrolase. Bioorg Med Chem Lett 22:601–605. doi:10.1016/j.bmcl.2011.10.074 CrossRefPubMedGoogle Scholar
  45. Pecic S, Pakhomova S, Newcomer ME et al (2013) Synthesis and structure-activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors. Bioorg Med Chem Lett 23:417–421. doi:10.1016/j.bmcl.2012.11.084 CrossRefPubMedGoogle Scholar
  46. Qiu H, Li N, Liu JY, Harris TR, Hammock BD, Chiamvimonvat N (2011) Soluble epoxide hydrolase inhibitors and heart failure. Cardiovas Ther 29:99–111. doi:10.1111/j.1755-5922.2010.00150.x CrossRefGoogle Scholar
  47. Rose TE, Morisseau C, Liu JY, Inceoglu B, Jones PD, Sanborn JR, Hammock BD (2010) 1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain. J Med Chem 53:7067–7075. doi:10.1021/jm100691c CrossRefPubMedPubMedCentralGoogle Scholar
  48. Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327–341. doi:10.1016/0021-9991(77)90098-5 CrossRefGoogle Scholar
  49. Sadowski J, Gasteiger J, Klebe G (1994) Comparison of automatic three-dimensional model builders using 630 X-ray structures. J Chem Inf Comp Sci 34:1000–1008. doi:10.1021/ci00020a039 CrossRefGoogle Scholar
  50. Schiøtt B, Bruice TC (2002) Reaction mechanism of soluble epoxide hydrolase: insights from molecular dynamics simulations. J Am Chem Soc 124:14558–14570. doi:10.1021/ja021021r CrossRefPubMedGoogle Scholar
  51. Shen HC (2010) Soluble epoxide hydrolase inhibitors: a patent review. Expert Opin Ther Pat 20:941–956. doi:10.1517/13543776.2010.484804 CrossRefPubMedGoogle Scholar
  52. Shen HC, Ding FX, Wang S et al (2009) Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent, selective and bioavailable soluble epoxide hydrolase inhibitors. Bioorg Med Chem Lett 19:3398–3404. doi:10.1016/j.bmcl.2009.05.036 CrossRefPubMedGoogle Scholar
  53. Tanaka D, Tsuda Y, Shiyama T et al (2011) A practical use of ligand efficiency indices out of the fragment-based approach: ligand efficiency-guided lead identification of soluble epoxide hydrolase inhibitors. J Med Chem 54:851–857. doi:10.1021/jm101273e CrossRefPubMedGoogle Scholar
  54. Tran KL, Aronov PA, Tanaka H, Newman JW, Hammock BD, Morisseau C (2005) Lipid sulfates and sulfonates are allosteric competitive inhibitors of the N-terminal phosphatase activity of the mammalian soluble epoxide hydrolase. Biochemistry 44:12179–12187. doi:10.1021/bi050842g CrossRefPubMedPubMedCentralGoogle Scholar
  55. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461. doi:10.1002/jcc.21334 PubMedPubMedCentralGoogle Scholar
  56. Wang J, Morin P, Wang W, Kollman PA (2001) Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA. J Am Chem Soc 123:5221–5230. doi:10.1021/ja003834q CrossRefPubMedGoogle Scholar
  57. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25:1157–1174. doi:10.1002/jcc.20035 CrossRefPubMedGoogle Scholar
  58. Waszkowycz B, Clark DE, Gancia E (2011) Outstanding challenges in protein-ligand docking and structure-based virtual screening. WIREs: Comput Mol Sci 1:229–259 doi:10.1002/wcms.18
  59. Weiner SJ, Kollman PA, Case DA et al (1984) A new force field for molecular mechanical simulation of nucleic acids and proteins. J Am Chem Soc 106:765–784. doi:10.1021/ja00315a051 CrossRefGoogle Scholar
  60. The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLCGoogle Scholar
  61. Yamada T, Morisseau C, Maxwell JE, Argiriadi MA, Christianson DW, Hammock BD (2000) Biochemical evidence for the involvement of tyrosine in epoxide activation during the catalytic cycle of epoxide hydrolase. J Biol Chem 275:23082–23088. doi:10.1074/jbc.M001464200 CrossRefPubMedGoogle Scholar
  62. Yu Z, Xu F, Huse LM et al (2000) Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circ Res 87:992–998. doi:10.1161/01.res.87.11.992 CrossRefPubMedGoogle Scholar
  63. Yuriev E, Ramsland PA (2013) Latest developments in molecular docking: 2010-2011 in review. J Mol Recognit 26:215–239. doi:10.1002/jmr.2266 CrossRefPubMedGoogle Scholar
  64. Yuriev E, Holien J, Ramsland PA (2015) Improvements, trends, and new ideas in molecular docking: 2012-2013 in review. J Mol Recognit 28:581–604. doi:10.1002/jmr.2471 CrossRefPubMedGoogle Scholar
  65. Zavareh E, Hedayati M, Rad L, Kiani A, Shahhosseini S, Faizi M, Tabatabai S (2014) Design, synthesis and biological evaluation of some oxadiazole derivatives as novel amide-based inhibitors of soluble epoxide hydrolase. Lett Drug Des Discov 11:721–730. doi:10.2174/1570180811666140220005530 CrossRefGoogle Scholar
  66. Zwanzig RW (1954) High-temperature equation of state by a perturbation method. I. nonpolar gases. J Chem Phys 22:1420–1426. doi:10.1063/1.1740409 CrossRefGoogle Scholar

Copyright information

© European Biophysical Societies' Association 2016

Authors and Affiliations

  • Leila Karami
    • 1
    • 2
  • Ali Akbar Saboury
    • 1
  • Elham Rezaee
    • 3
  • Sayyed Abbas Tabatabai
    • 3
  1. 1.Institute of Biochemistry and BiophysicsUniversity of TehranTehranIran
  2. 2.Department of Cell and Molecular Biology, Faculty of Biological SciencesKharazmi UniversityTehranIran
  3. 3.Department of Pharmaceutical Chemistry, School of PharmacyShahid Beheshti University of Medical SciencesTehranIran

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