Prediction of water–octanol partition coefficients using theoretical descriptors derived from the molecular surface area and the electrostatic potential

Abstract

Octanol–water partition coefficients are frequently used in quantitative structure–activity relationships. A correlation based on computed theoretical descriptors is presented for the prediction of octanol–water partition coefficients (P_ow). An ab initio SCF approach was used to compute the molecular descriptors at the HF/6-31G* level. It was shown that only three theoretical parameters representing a cavity term, a dipolarity/polarisability term and a hydrogen bonding term were needed for the correlation. The corresponding parameters were deduced from the molecular surface area, the surface electrostatic potential and the spatial minima of the electrostatic potential, respectively. The predictive power of log P_ow was demonstrated on a number of molecules which have biological activity.

References

1. C. Hansch and A. Leo, Exploring QSAR: Fundamentals and Applications in Chemistry and Biology, ACS, Washington DC, 1995.
2. A. Leo, P. Y. C. Jow, C. Silipo and C. Hansch, J. Med. Chem., 1975, 18, 865.
3. M. J. Kamlet, J. L. M. Abboud and R. W. Taft, Progr. Phys. Org. Chem., 1981, 13, 485.
4. M. J. Kamlet, R. M. Doherty, M. H. Abraham, Y. H. Marcus and R. W. Taft, J. Phys. Chem., 1988, 92, 5244.
5. M. H. Abraham, P. L. Grellier, D. V. Prior, J. J. Morris, P. J. Taylor, C. Laurence and M. Berthelot, Tetrahedron Lett., 1989, 30, 521.
6. M. H. Abraham, P. L. Grellier, D. V. Prior, J. J. Morris and P. J. Taylor, J. Chem. Soc., Perkin Trans. 2, 1990, 521.
7. M. H. Abraham, P. P. Duce, P. L. Grellier, D. V. Prior, J. J. Morris and P. J. Taylor, Tetrahedron Lett., 1988, 29, 1587.
8. M. H. Abraham, P. L. Grellier, D. V. Prior, P. P. Duce, J. J. Morris and P. J. Taylor, J. Chem. Soc., Perkin Trans. 2, 1989, 699.
9. N. Bodor, Z. Gabanyi and C.-K. Wong, J. Am. Chem. Soc., 1989, 111, 3783.
10. N. Bodor and M.-J. Huang, J. Pharm. Sci., 1992, 81, 272.
11. Y. Sasaki, H. Kubodera, T. Matsuszaki and H. Umeyama, J. Pharmacobio-Dyn., 1991, 14, 207.
12. G. R. Famini and L. Y. Wilson, in Quantitative Treatments of Solute/Solvent Interactions, eds. P. Politzer and J. S. Murray, Elsevier, Amsterdam, 1994.
13. G. R. Famini, C. A. Penski and L. Y. Wilson, J. Phys. Org. Chem., 1992, 5, 395.
14. T. Brinck, J. S. Murray and P. Politzer, J. Org. Chem., 1993, 58, 7070.
15. H. Hagelin, J. S. Murray, T. Brinck, M. Berthelot and P. Politzer, Can. J. Chem., 1995, 73, 483.
16. J. S. Murray, P. Lane, T. Brinck, K. Paulsen, M. E. Grice and P. Politzer, J. Phys. Chem., 1993, 97, 9369.
17. P. Politzer, P. Lane, J. S. Murray and T. Brinck, J. Phys. Chem., 1992, 96, 7938.
18. J. S. Murray, S. Ranganathan and P. Politzer, J. Org. Chem., 1991, 56, 3734.
19. J. S. Murray and P. Politzer, J. Chem. Res. (S), 1992, 110.
20. T. Brinck, J. S. Murray and P. Politzer, Mol. Phys., 1992, 76, 609.
21. J. S. Murray, T. Brinck, P. Lane, K. Paulsen and P. Politzer, J. Mol. Struct. (Theochem), 1994, 307, 55.
22. J. S. Murray and P. Politzer, in Quantitative Treatments of Solute/Solvent Interactions, eds. P. Politzer and J. S. Murray, Elsevier, Amsterdam, 1994.
23. U. Dinur and A. T. Hagler, in Reviews in Computational Chemistry, eds. K. B. Lipkowitz and D. B. Boyd, VCH, New York 1991.
24. S. Scheiner, in Reviews in Computational Chemistry, eds. K. B. Lipkowitz and D. B. Boyd, VCH, New York, 1991.
25. P. Sjoberg, J. S. Murray, T. Brinck and P. Politzer, Can. J. Chem., 1990, 68, 1440.
26. T. A. Koopmans, Physica, 1933, 1, 104.
27. T. Brinck, J. S. Murray and P. Politzer, Int. J. Quantum Chem., 1993, 48, 73.
28. T. Brinck, unpublished results.
29. M. J. Frisch, G. W. Trucks, H. B. Schlegel, P. M. W. Gill, B. G. Johnson, M. A. Robb, J. R. Cheeseman, T. A. Keith, G. A. Petersson, J. A. Montgomery, K. Raghavachari, M. A. Al-Laham, V. G. Zakrzewski, J. V. Ortiz, J. B. Foresman, C. Y. Peng, P. Y. Ayala, W. Chen, M. W. Wong, J. L. Andres, E. S. Replogle, R. Gomperts, R. L. Martin, D. J. Fox, J. S. Binkley, D. J. Defrees, J. Baker, J. P. Stewart, M. Head-Gordon, C. Gonzalez and J. A. Pople, GAUSSIAN 94 (Revision B.3), Gaussian Inc., Pittsburgh PA, 1995.
30. W. J. Hehre, L. Radom, P. v. R. Schleyer and J. A. Pople, Ab Initio Molecular Orbital Theory, John Wiley, New York, 1986.
31. T. Brinck, J. S. Murray and P. Politzer, J. Org. Chem., 1991, 56, 5012.
32. J. S. Murray, T. Brinck and P. Politzer, Int. J. Quantum Chem., Quantum Biol. Symp., 1991, 18, 91.
33. M. Haeberlein and T. Brinck, J. Phys. Chem., 1996, 100, 10 116.
34. R. F. W. Bader and H. J. T. Preston, Theoret. Chim. Acta, 1970, 17, 384.
35. R. F. W. Bader, M. T. Carroll, J. R. Cheeseman and C. Chang, J. Am. Chem. Soc., 1987, 109, 7968.
36. P. Camilleri, S. A. Watts and J. A. Boraston, J. Chem. Soc., Perkin Trans. 2, 1988, 1699.
37. D. E. Leahy, J. J. Morris, P. J. Taylor and A. R. Wait, J. Chem. Soc., Perkin Trans. 2, 1992, 705.
38. B. Y. Simkin and I. I. Sheikhet, Quantum Chemical and Statistical Theory of Solutions: A Computational Approach, Ellis Horwood, London, 1995.
39. T. Brinck, J. S. Murray and P. Politzer, J. Chem. Phys., 1993, 98, 4305.
40. J. Israelachvili, Intermolecular and Surface Forces, Academic, London, 2nd edn., 1992.
41. T. Brinck, unpublished results.
42. C. Hansch, A. Leo and D. Hoekman, Exploring QSAR: Hydrophobic, Electronic, and Steric Constants, ACS, Washington, DC, 1995.
43. C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology, Wiley, New York, 1979.