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Calculation of binding affinities of HIV-1 RT and β-secretase inhibitors using the linear interaction energy method with explicit and continuum solvation approaches

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Abstract

The linear interaction energy (LIE) approach has been applied to estimate the binding free energies of representative sets of HIV-1 RT and β-Secretase inhibitors, using both molecular dynamics (MD) and tethered energy minimization sampling protocols with the OPLS-AA potential, using a range of solvation methodologies. Generalized Born (GB), ‘shell’ and periodic boundary condition (PBC) solvation were used, the latter with reaction field (RF) electrostatics. Poisson-Boltzmann (PB) and GB continuum electrostatics schemes were applied to the simulation trajectories for each solvation type to estimate the electrostatic ligand-water interaction energy in both the free and bound states. Reasonable agreement of the LIE predictions was obtained with respect to experimental binding free energy estimates for both systems: for instance, ‘PB’ fits on MD trajectories carried out with PBC solvation and RF electrostatics led to models with standard errors of 1.11 and 1.03 kcal mol−1 and coefficients of determination, r 2 of 0.76 and 0.75 for the HIV-1 RT and β-Secretase sets. However, it was also found that results from MD sampling using PBC solvation provided only slightly better fits than from simulations using shell or Born solvation or tethered energy minimization sampling.

Evolution of the running averages for compound H11 (binding to HIV-1RT) of the bound state ligand-water and ligand-protein interaction energies. The ligand-water electrostatic terms are twice the corresponding GB and PB electrostatic solvation free energies. The ligand-receptor van der Waals and Coulombic interaction energies are also shown, in addition to the ligand-water van der Waals interaction term. The terms were calculated (without application of a cut-off) from a trajectory sampled under PBC solvation with reaction field electrostatics

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References

  1. Lazaridis T (2002) Curr Org Chem 6:1319–1332

    Article  CAS  Google Scholar 

  2. Muegge I (2000) Perspect Drug Discovery Des 20:99–114

    Article  CAS  Google Scholar 

  3. Stahl M, Rarey M (2001) J Med Chem 44:1035–1042

    Article  CAS  Google Scholar 

  4. Pearlman DA, Charifson PS (2001) J Med Chem 44:3417–3423

    Article  CAS  Google Scholar 

  5. Beveridge DL, Dicapua FM (1989) Ann Rev Biophys Chem 18:431–492

    Article  CAS  Google Scholar 

  6. Straatsma TP, McCammon JA (1992) Ann Rev Phys Chem 43:407–435

    Article  CAS  Google Scholar 

  7. Kollman PA (1993) Chem Rev 93:2395–2417

    Article  CAS  Google Scholar 

  8. Pearlman DA, Rao BG (1998) Encyl Comput Chem 1036–1061

  9. Woods CJ, Essex JW, King MA (2003) J Phys Chem B 107:13703–13710

    Article  CAS  Google Scholar 

  10. Jayachandran G, Shirts MR, Park S, Pande VS (2006) J Chem Phys 125:084901

    Article  Google Scholar 

  11. Åqvist J, Medina C, Samuelsson JE (1994) Protein Eng 7:385–391

    Article  Google Scholar 

  12. Hansson T, Åqvist J (1995) Protein Eng 8:1137–1144

    Article  CAS  Google Scholar 

  13. Åqvist J, Hansson T (1996) J Phys Chem 100:9512–9521

    Article  Google Scholar 

  14. Åqvist J (1996) J Comp Chem 17:1587–1597

    Article  Google Scholar 

  15. Carlson HA, Jorgensen WL (1995) J Phys Chem 99:10667–10673

    Article  CAS  Google Scholar 

  16. Jones-Hertzog DK, Jorgensen WL (1997) J Med Chem 40:1539–1549

    Article  CAS  Google Scholar 

  17. Marelius J, Graffner-Nordberg M, Hansson T, Hallberg A, Åqvist J (1998) J Comput-Aided Mol Des 12:119–131

    Article  CAS  Google Scholar 

  18. Smith RH Jr, Jorgensen WL, Tirado-Rives J, Lamb ML, Janssen PAJ, Michejda CJ, Smith MBK (1998) J Med Chem 41:5272–5286

    Article  CAS  Google Scholar 

  19. Hansson T, Marelius J, Åqvist J (1998) J Comput-Aided Mol Des 12:27–35

    Article  CAS  Google Scholar 

  20. Wall ID, Leach AR, Salt DW, Ford MG, Essex JW (1999) J Med Chem 42:5142–5152

    Article  CAS  Google Scholar 

  21. Wang W, Wang J, Kollman PA (1999) Proteins: Struct, Funct, Genet 34:395–402

    Article  CAS  Google Scholar 

  22. Lamb ML, Tirado-Rives J, Jorgensen WL (1999) Biorg Med Chem 7:851–860

    Article  CAS  Google Scholar 

  23. Sham YY, Chu ZT, Tao H, Warshel A (2000) Proteins: Struct, Funct, Genet 39:393–407

    Article  CAS  Google Scholar 

  24. Chen J, Wang R, Taussig M, Houk KN (2001) J Org Chem 66:3021–3026

    Article  CAS  Google Scholar 

  25. Hou TJ, Zhang W, Xu XJ (2001) J Phys Chem B 105:5304–5315

    Article  CAS  Google Scholar 

  26. Zhou R, Friesner RA, Ghosh A, Rizzo RC, Jorgensen WL, Levy RM (2001) J Phys Chem B 105:10388–10397

    Article  CAS  Google Scholar 

  27. Åqvist J, Marelius J (2001) Comb Chem High Throughput Screening 4:613–626

    Google Scholar 

  28. Tounge BA, Reynolds CH (2003) J Med Chem 46:2074–2082

    Article  CAS  Google Scholar 

  29. Svab I, Alexandru D, Vitos G, Flonta ML (2004) J Cell Mol Med 8:551–562

    Article  CAS  Google Scholar 

  30. Schrøder Leiros H-K et al (2004) Protein Sci 13:1056–1070

    Article  Google Scholar 

  31. Carlsson J, Andér M, Nervall M, Åqvist J (2006) J Phys Chem B 110:12034–12041

    Article  CAS  Google Scholar 

  32. Åqvist J (1990) J Phys Chem 94:8021–8024

    Article  Google Scholar 

  33. Roux B, Yu H-A, Karplus M (1990) J Phys Chem 94:4683–4688

    Article  CAS  Google Scholar 

  34. Zhou Z, Madura JD (2004) Proteins: Struct Funct Genet 57:493–503

    Article  CAS  Google Scholar 

  35. Lee FS, Warshel A (1992) J Chem Phys 97:3100–3107

    Article  CAS  Google Scholar 

  36. Tanaka H et al (1991) J Med Chem 34:349–357

    Article  CAS  Google Scholar 

  37. Tanaka H et al (1992) J Med Chem 35:346–350

  38. Tanaka H et al (1992) J Med Chem 35:4713–4719

    Article  CAS  Google Scholar 

  39. Tanaka H et al (1995) J Med Chem 38:2860–2865

    Article  CAS  Google Scholar 

  40. Hopkins AL, Ren J, Esnouf RM, Willcox BE, Jones EY, Ross C, Miyasaka T, Walker RT, Tanaka H, Stammers DK, Stuart DI (1996) J Med Chem 39:1589–1600

    Article  CAS  Google Scholar 

  41. Ghosh AK, Bilcer G, Harwood C, Kawahama R, Shin D, Hussain KA, Hong L, Loy JA, Nguyen C, Koelsch G, Ermolieff J, Tang J (2001) J Med Chem 44:2865–2868

    Article  CAS  Google Scholar 

  42. Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC, Tang J (2000) Science 290:150–153

    Article  CAS  Google Scholar 

  43. Hong L, Turner RT, Koelsch G, Shin D, Ghosh AK, Tang J (2002) Biochemistry 41:10963–10967

    Article  CAS  Google Scholar 

  44. MOE: The Molecular Operating Environment from Chemical Computing Group Inc., 1010 Sherbrooke St. W., Suite 910, Montréal, Québec, Canada H3A 2R7

  45. Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) J Am Chem Soc 117:11225–11236

    Article  Google Scholar 

  46. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) J Chem Phys 79:926–935

    Article  CAS  Google Scholar 

  47. Onufriev A, Bashford D, Case DA (2000) J Phys Chem B 104:3712–3720

    Article  CAS  Google Scholar 

  48. Hawkins GD, Cramer CJ, Truhlar DG (1995) Chem Phys Lett 246:122–129

    Article  CAS  Google Scholar 

  49. van Gunsteren WF, Berendsen HJC (1990) Angew Chem Int Ed Engl 29:992–1023

    Article  Google Scholar 

  50. Hart TN, Read RJ (1992) Proteins: Struct Funct Genet 13:206–222

    Article  CAS  Google Scholar 

  51. Neumann M (1985) J Chem Phys 82:5663–5672

    Article  CAS  Google Scholar 

  52. Lekner J (1989) Physica A157:826; Lekner J (1991) Physica A157:826–838

  53. English NJ, MacElroy JMD (2002) Molec Phys 100:3753–3769

    Article  CAS  Google Scholar 

  54. English NJ, Sorescu DC, Johnson JK (2006) J Phys Chem Solids 67:1399–1409

    Article  CAS  Google Scholar 

  55. Allen MP, Tildesley DJ (1987) Computer Simulation of Liquids. Clarendon, Oxford

    Google Scholar 

  56. Izaguirre JA, Reich S, Skeel RD (1999) J Chem Phys 110:9853–9864

    Article  CAS  Google Scholar 

  57. Grant JA, Pickup BT, Nicholls A (2001) J Comput Chem 22:608–640

    Article  CAS  Google Scholar 

  58. Rizzo RC, Aynechi T, Case DA, Kuntz ID (2006) J Chem Theory Comput 2:128–139

    Article  CAS  Google Scholar 

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Acknowledgements

The author acknowledges useful discussions with Dr. Jonathan Heal (Prosarix Ltd.).

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  1. Niall J. English

    Present address: School of Chemical and Bioprocess Engineering, The Centre for Synthesis and Chemical Biology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland

Authors and Affiliations

  1. Chemical Computing Group, St. John’s Innovation Centre, Cambridge, CB4 0WS, Great Britain

    Niall J. English

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Correspondence to Niall J. English.

Electronic supplementary material

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ESM 1

Tables of the overall LIE terms for all HIV-1RT and BACE ligands for each sampling method. (DOC 187 kb)

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English, N.J. Calculation of binding affinities of HIV-1 RT and β-secretase inhibitors using the linear interaction energy method with explicit and continuum solvation approaches. J Mol Model 13, 1081–1097 (2007). https://doi.org/10.1007/s00894-007-0229-0

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  • DOI: https://doi.org/10.1007/s00894-007-0229-0

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