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Modeling The Effect of Solvation on Structure, Reactivity, and Partitioning of Organic Solutes: Utility in Drug Design

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Rational Drug Design

Part of the book series: The IMA Volumes in Mathematics and its Applications ((IMA,volume 108))

Abstract

The SMx family of quantum mechanical solvation models accounts for electric and electronic polarization via the generalized Born model and for non-electrostatic components of solvation by microscopic surface tensions. The SM5.4 model, which is the most physical member of the SMx family, has been parameterized using two electronic Hamiltonians, AM1 and PM3. For both Hamiltonians, solvation parameters are obtained for water and for any organic solvent for which certain macroscopic data are available, in particular, the index of refraction, bulk surface tension, dielectric constant, and hydrogen bonding acidity and basicity as measured by the Abraham empirical α H2 and β H2 scales. For neutral solutes, the mean unsigned errors for aqueous and non-aqueous free energies of solvation are both 0.5 kcal / mol based on 215 and 1786 data points, respectively (for either Hamiltonian). By adding solvation effects to the gas-phase Hamiltonian, it is possible to model the effects of solvent on conformational analysis, molecular recognition, reaction kinetics, etc. The SM5.4 model is also useful for the calculation of solute partitioning between two solvents. Moreover, it is possible to generalize the SM5.4 model to media that are less well characterized than homogeneous solvents—an example is presented here for the case of bilayers of phosphatidyl choline—in order to model partitioning between biophases.

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References

  1. Hansch, C.; Fujita, T., J. Am. Chem. Soc., 1964, 86, 1616.

    Article  Google Scholar 

  2. Silverman, R.B., The Organic Chemistry of Drug Design and Drug Action, Academic: San Diego, 1992, 26–34.

    Google Scholar 

  3. Chambers, C.C.; Hawkins, G.D.; Cramer, C.J.; Truhlar, D.G., J. Phys. Chem., 1996, 100, 16385.

    Article  Google Scholar 

  4. Giesen, D.J.; Gu, M.Z.; Cramer, C.J.; Truhlar, D.G., J. Org. Chem., 1996, 61, 8720.

    Article  Google Scholar 

  5. Hawkins, G.D.; Cramer, C.J.; Truhlar, D.G., J. Phys. Chem., 1996, 100, 19824.

    Article  Google Scholar 

  6. Giesen, D.J.; Chambers, C.C.; Cramer, C.J.; Truhlar, D.G., J. Phys. Chem., 1997, 101, 2061.

    Google Scholar 

  7. Giesen, D.J.; Hawkins, G.D.; Liotard, D.A.; Cramer, C.J.; Truhlar, D.G., Theor. Chem. Acc., in press.

    Google Scholar 

  8. Hawkins, G.D.; Cramer, C.J.; Truhlar, D.G., to be published.

    Google Scholar 

  9. Cramer, C.J., Truhlar, D.G., J. Am. Chem. Soc., 1991, 113, 8305.

    Article  Google Scholar 

  10. Cramer, C.J.; Truhlar, D.G., J. Comput.-Aid. Mol. Des., 1992, 6, 629.

    Article  Google Scholar 

  11. Cramer, C.J.; Truhlar, D.G., In Quantitative Treatments of Solute/Solvent Interactions; Politzer, P. and Murray, J.S., Eds.; Elsevier: Amsterdam, 1994, 1, 9.

    Google Scholar 

  12. Cramer, C.J.; Truhlar, D.G., In Reviews in Computational Chemistry; Lipkowitz, K.B. and Boyd, D.B., Eds.; VCH: New York, 1995, 6, 1.

    Chapter  Google Scholar 

  13. Cramer, C.J.; Truhlar, D.G., In Solvent Effects and Chemical Reactivity; Tapia, O. and Bertrán, J., Eds.; Kluwer: Dordrecht, 1996, 1.

    Google Scholar 

  14. Cramer, C.J.; Truhlar, D.G., Science, 1992, 256, 213.

    Article  Google Scholar 

  15. Cramer, C.J.; Truhlar, D.G., J. Comp. Chem., 1992, 13, 1089.

    Article  Google Scholar 

  16. Storer, J.W.; Giesen, D.J.; Hawkins, G.D.; Lynch, G.C.; Cramer, C.J.; Truhlar, D.G.; Liotard, D.A., In Structure and Reactivity in Aqueous Solution; Cramer, C.J. and Truhlar, D.G., Eds.; American Chemical Society: Washington, DC, 1994, 24.

    Chapter  Google Scholar 

  17. Liotard, D.A.; Hawkins, G.D.; Lynch, G.C.; Cramer, C.J.; Truhlar, D.G., J. Comp. Chem., 1995, 16, 422.

    Article  Google Scholar 

  18. Hawkins, G.D.; Cramer, C.J.; Truhlar, D.G., Chem. Phys. Lett., 1995, 246, 122.

    Article  Google Scholar 

  19. Barrows, S.E.; Dulles, F.J.; Cramer, C.J.; Truhlar, D.G.; French, A.D., Carbohydr. Res., 1995, 276, 219.

    Article  Google Scholar 

  20. Giesen, D.J.; Cramer, C.J.; Truhlar, D.G., J. Phys. Chem., 1995, 99, 7137.

    Article  Google Scholar 

  21. Giesen, D.J.; Storer, J.W.; Cramer, C.J.; Truhlar, D.G., J. Am. Chem. Soc., 1995, 117, 1057.

    Article  Google Scholar 

  22. Dewar, M.J.S.; Zoebisch, E.G.; Healy, E.F.; Stewart, J.J.P., J. Am. Chem. Soc., 1985, 107, 3902.

    Article  Google Scholar 

  23. Dewar, M.J.S.; Zoebisch, E.G., J. Mol. Struct. (Theochem), 1988, 180, 1.

    Article  Google Scholar 

  24. Dewar, M.J.S.; Yate-Ching, Y., Inorg. Chem., 1990, 29, 3881.

    Article  Google Scholar 

  25. Stewart, J.J.P., J. Comp. Chem., 1989, 10, 221.

    Article  Google Scholar 

  26. Hoijtink, G.J.; De Boer, E.; Van Der Meij, P.H.; Weijland, W.P., Red. Tray. Chim. Pays-Bas, 1956, 75, 487.

    Article  Google Scholar 

  27. Peradejordi, F., Cahiers Phys., 1963, 17, 343.

    Google Scholar 

  28. Jano, I., Compt. Rend. Acad. Sci. Paris, 1965, 261, 103.

    Google Scholar 

  29. Klopman, G., Chem. Phys. Lett., 1967, 1, 200.

    Article  Google Scholar 

  30. Tapia, O., In Quantum Theory of Chemical Reactions; Daudel, R., Pullman, A., Salem, L. and Viellard, A., Eds.; Reidel: Dordrecht, 1980, 2, 25.

    Chapter  Google Scholar 

  31. Constanciel, R.; Contreras, R., Theor. Chim. Acta, 1984, 65, 1.

    Article  Google Scholar 

  32. Contreras, R.; Aizman, A., Int. J. Quant. Chem., 1985, 27, 293.

    Article  Google Scholar 

  33. Kozaki, T.; Morihashi, M.; Klxuchi, O., J. Am. Chem. Soc., 1989, 111, 1547.

    Article  Google Scholar 

  34. Tucker, S.C.; Truhlar, D.G., Chem. Phys. Lett., 1989, 157, 164.

    Article  Google Scholar 

  35. Still, W.C.; Tempczyk, A.; Hawley, R.C.; Hendrickson, T., J. Am. Chem. Soc., 1990, 112, 6127.

    Article  Google Scholar 

  36. King, P.M., In Computer Simulation of Biornolecular Systems; van Gunsteren, W.F., Weinger, P.K. and Wilkinson, A.J., Eds.; ESCOM: Leiden, 1993, 2, 267.

    Google Scholar 

  37. Kikuchi, O.; Matsuoka, T.; Sawahata, H.; Takahashi, O., J. Mol. Struct. (Theochem), 1994, 305, 79.

    Article  Google Scholar 

  38. Storer, J.W.; Giesen, D.J.; Cramer, C.J.; Truhlar, D.G., J. Comput.-Aid. Mol. Des., 1995, 9, 87.

    Article  Google Scholar 

  39. Mulliken, R.S., J. Chem. Phys., 1955, 23, 1833.

    Article  Google Scholar 

  40. Singh, U.C.; Kollman, P.A., J. Comp. Chem.,1984, 5, 129.

    Article  Google Scholar 

  41. Besler, B.H.; Merz, K.M.; Kollman, P.A., J. Comp. Chem., 1990, 11, 431.

    Article  Google Scholar 

  42. Merz, K.M., J. Comp. Chem., 1992, 13, 749.

    Article  Google Scholar 

  43. Cornell, W.D.; Cieplak, P.; Bayly, C.I.; Kollman, P.A., J. Am. Chem. Soc., 1993, 115, 9620.

    Article  Google Scholar 

  44. Dewar, M.J.S.; Thiel, W., J. Am. Chem. Soc., 1977, 99, 4899.

    Article  Google Scholar 

  45. Thiel, W.; Voityuk, A.A., Int. J. Quant. Chem., 1992, 44, 807.

    Article  Google Scholar 

  46. Thiel, W.; Voityuk, A.A., Theor. Chim. Acta, 1992, 81, 391.

    Article  Google Scholar 

  47. Kolb, M.; Thiel, W., J. Comp. Chem., 1993, 14, 775.

    Article  Google Scholar 

  48. Schaefer, M.; Froemmel, C., J. Mol. Biol., 1990, 216, 1045.

    Article  Google Scholar 

  49. Lee, B.; Richards, F.M., J. Mol. Biol., 1971, 55, 379.

    Article  Google Scholar 

  50. Abraham, M.H.; Grellier, P.L.; Prior, D.V.; Duce, P.P.; Morris, J.J.; Taylor, P., J. Chem. Soc. Perkin Trans., 1989, 2, 699.

    Google Scholar 

  51. Abraham, M.H., Chem. Soc. Rev., 1993, 73.

    Google Scholar 

  52. Abraham, M.H., In Quantitative Treatments of Solute/Solvent Interactions; Politzer, P. and Murray, J.S., Eds.; Elsevier: Amsterdam, 1994, 83.

    Google Scholar 

  53. Cramer, C.J.; Truhlar, D.G., J. Am. Chem. Soc., 1991, 113, 8552 and 9901(E).

    Article  Google Scholar 

  54. Cramer, C.J.; Truhlar, D.G., J. Am. Chem. Soc., 1993, 115, 8810.

    Article  Google Scholar 

  55. Contreras, J.G.; Alderete, J.B., J. Mol. Struct. (Theochem), 1994, 309, 137.

    Article  Google Scholar 

  56. Cramer, C.J.; Truhlar, D.G., J. Am. Chem. Soc., 1993, 115, 5745.

    Article  Google Scholar 

  57. Yang, B.; Wright, J.; Eldefrawi, M.E.; Pou, S.; Mackerell, A.D., J. Am. Chem. Soc., 1994, 116, 8722.

    Article  Google Scholar 

  58. Rao, B.G.; Kim, E.E.; Murcko, M.A., J. Comput.-Aid. Mol. Des., 1996, 10, 23.

    Article  Google Scholar 

  59. Urban, J.J.; Cramer, C.J.; Famini, G.R., J. Am. Chem. Soc., 1992, 114, 8226.

    Article  Google Scholar 

  60. Barrows, S.E.; Cramer, C.J.; Truhlar, D.G.; Weber, E.J.; Elovitz, M.S., Environ. Sci. Technol., 1996, 30, 3028.

    Article  Google Scholar 

  61. Chambers, C.C.; Archibong, E.F.; Jabalameli, A.; Sullivan, R.H.; Giesen, D.J.; Cramer, C.J.; Truhlar, D.G., J. Mol. Struct. (Theochem), in press.

    Google Scholar 

  62. Cramer, C.J.; Truhlar, D.G., J. Am. Chem. Soc., 1994, 116, 3892.

    Article  Google Scholar 

  63. Mckee, M.L., J. Phys. Chem., 1993, 97, 13608.

    Article  Google Scholar 

  64. Severance, D.L.; Jorgensen, W.L., In Structure and Reactivity in Aqueous Solution; Cramer, C.J. and Truhlar, D.G., Eds.; American Chemical Society: Washington, DC, 1994, 568, 243.

    Chapter  Google Scholar 

  65. Angyal, S.J., Aust. J. Chem., 1968, 21, 2737.

    Article  Google Scholar 

  66. Ha, S.N.; Giammona, A.; Field, M.; Brady, J.W., Carbohydr. Res., 1988, 180, 207.

    Article  Google Scholar 

  67. Brady, J.W., J. Am. Chem. Soc., 1989, 111, 5155.

    Article  Google Scholar 

  68. Kroon-Batenburg, L.M.J.; Kroon, J., Biopolymers, 1990, 29, 1243.

    Article  Google Scholar 

  69. Van Eijck, B.P.; Kroon-Batenburg, L.M. J.; Kroon, J., J. Mol. Struct.., 1990, 237, 315.

    Article  Google Scholar 

  70. Ha, S.; Gao, J.; Tidor, B.; Brady, J.W.; Karplus, M., J. Am. Chem. Soc.., 1991, 113, 1553.

    Article  Google Scholar 

  71. Zhbankov, R.G., J. Mol. Struct., 1992, 275, 645.

    Article  Google Scholar 

  72. Polavarapu, P.L.; Ewig, C.S., J. Comp. Chem., 1992, 13, 1255.

    Article  Google Scholar 

  73. Van Eijck, B.P.; Hooft, R.W.W.; Kroon, J., J. Phys. Chem., 1993, 97, 12093.

    Google Scholar 

  74. Glennon, T.M.; Zheng, Y.J.; le Grand, S.M.; Shutzberg, B.A.; Merz, K.M., JR.J. Comp. Chem., 1994, 15, 1019.

    Article  Google Scholar 

  75. Dowd, M.K.; French, A.D.; Reilly, P.J., Carbohydr. Res., 1994, 264, 1.

    Article  Google Scholar 

  76. Zuccarello, F.; Buemi, G., Carbohydr. Res., 1995, 273, 129.

    Article  Google Scholar 

  77. Hehre, W.J.; Radom, L.; Schleyer, P.v.R.; Pople, J.A., Ab Initio Molecular Orbital Theory; Wiley: New York, 1986.

    Google Scholar 

  78. Barrows, S.E.; Storer, J.W.; Cramer, C.J.; Truhlar, D.G.; French, A.D., J. Comp. Chem., in press.

    Google Scholar 

  79. Angyal, S.J., Angew. Chem. Int. Ed. Engl., 1969, 8, 157.

    Article  Google Scholar 

  80. Cramer, C.J.; Truhlar, D.G.; French, A.D., Carbohydr. Res., 1997, 298, 1.

    Article  Google Scholar 

  81. Kirkwood, J.G., J. Chem. Phys., 1934, 2, 351.

    Article  Google Scholar 

  82. Onsager, L., J. Am. Chem. Soc., 1936, 58, 1486.

    Article  Google Scholar 

  83. Mícovíc, L.D.; Žigman, V., J. Chem. Soc. Perkin Trans. II, 1985, 625.

    Google Scholar 

  84. Denbigh, K., The Principles of Chemical Equilibrium, 4th ed., Cambridge University Press: London, 1981, 256–257.

    Book  Google Scholar 

  85. Ben-Naim, A., Statistical Thermodynamics for Chemists and Biochemists, Plenum: New York, 1992, 421.

    Google Scholar 

  86. Giesen, D.J.; Chambers, C.C.; Hawkins, G.D.; Cramer, C.J.; Truhlar, D.G., In Computational Thermochemistry: Prediction and Estimation of Molecular Thermodynamics; Irikura, K. and Frurip, D.J., Eds.; American Chemical Society: Washington, DC, in press.

    Google Scholar 

  87. Lombardo, F.; Blake, J.F.; Curatolo, W.J., J. Med. Chem., 1996, 39, 4750.

    Article  Google Scholar 

  88. Trohalaki, S.; Pachter, R., In Abstracts of the 211th National Meeting of the American Chemical Society; American Chemical Society: Washington, DC, 1996, COMP 60.

    Google Scholar 

  89. Ribadeneira, M.D.; Aungst, B.J.; Eyermann, C.J.; Huang, S.-M., Pharm. Res., 1996, 13, 227.

    Article  Google Scholar 

  90. Giesen, D.J.; Chambers, C.C.; Cramer, C.J.; Truhlar, D.G., J. Phys. Chem., in press.

    Google Scholar 

  91. Reynolds, C.H., J. Chem. Inf. Comput. Sci., 1995, 35, 738.

    Article  Google Scholar 

  92. Leo, A.J., Masterfile database (1994) from MedChem Software.

    Google Scholar 

  93. Vaes, W.H.J.; Urrestarazu Ramos, E.; Hamwijk, C.; Van Holsteijn, I.; Blaauboer, B.J.; Seinen, W.; Verhaar, H.J.M; Hermens, J.L.M., Chem. Res. Toxicol., 1997, 10, 1067.

    Article  Google Scholar 

  94. Wohlfarth, C., In CRC Handbook of Chemistry and Physics, 76th ed.; Lide, D.R., Ed.; CRC Press: Boca Raton, FL, 1995, 6–159ff.

    Google Scholar 

  95. Gonzalez-Lafont, A.; Truong, T.N.; Truhlar, D.G., J. Phys. Chem., 1991, 95, 4618.

    Article  Google Scholar 

  96. Liu, Y.-P.; Lu, D.-H.; Gonzalez-Lafont, A.; Truhlar, D.G.; Garrett, B.C., J. Am. Chem. Soc., 1993, 115, 7806.

    Article  Google Scholar 

  97. Bash, P.; Ho, L.L.; Mackerell, A.D.; Levine, D.; Hallstrom, P., Proc. Natl. Acad. Sci. USA, 1996, 93, 3698.

    Article  Google Scholar 

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Authors and Affiliations

  1. Departments of Physics and Chemistry, Mercyhurst College, 501 E. 38th St., Erie, PA, 16546, USA

    Candee C. Chambers

  2. Eastman Kodak Co., 1999 Lake Avenue, Rochester, NY, 14650, USA

    David J. Giesen

  3. Department of Chemistry and Supercomputer Institute, 207 Pleasant St. SE, Minneapolis, MN, 55455-0431, USA

    Gregory D. Hawkins, Christopher J. Cramer & Donald G. Truhlar

  4. Research Institute of Toxicology, Utrecht University, P.O. Box 80176, NL-3508, TD, Utrecht, The Netherlands

    Wouter H. J. Vaes

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  1. Candee C. Chambers
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Editor information

Editors and Affiliations

  1. Department of Chemistry, University of Minnesota, Minneapolis, MN, MN 55455-0431, USA

    Donald G. Truhlar

  2. Pharmacia & Upjohn Inc., Unit 7247-267-1, Kalamazoo, MI, 49001, USA

    W. Jeffrey Howe

  3. Department of Medicinal Chemistry and Pharmacognocy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612-7231, USA

    Anthony J. Hopfinger

  4. Metaphorics LLC, 130 Alta Avenue, Piedmont, CA, 94611, USA

    Jeff Blaney

  5. Department of Computer Science, Washington University, St. Louis, MO, 63130, USA

    Richard A. Dammkoehler

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Chambers, C.C., Giesen, D.J., Hawkins, G.D., Cramer, C.J., Truhlar, D.G., Vaes, W.H.J. (1999). Modeling The Effect of Solvation on Structure, Reactivity, and Partitioning of Organic Solutes: Utility in Drug Design. In: Truhlar, D.G., Howe, W.J., Hopfinger, A.J., Blaney, J., Dammkoehler, R.A. (eds) Rational Drug Design. The IMA Volumes in Mathematics and its Applications, vol 108. Springer, New York, NY. https://doi.org/10.1007/978-1-4612-1480-9_5

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