Toward basic understanding of the partition coefficient log P and its application in QSAR 1

¹Presented at CMTPI 2007: Computational Methods in Toxicology and Pharmacology Integrating Internet Resources (Moscow, Russia, September 1–5, 2007).

Abstract

The log P value has been the first choice for the molecular hydrophobicity descriptor in QSAR studies. However, it is still now difficult to understand the partitioning phenomenon in terms of physical chemistry. First, an attempt to understand and predict log P is addressed. We formulated a simple model that expressed by the solvent accessible surface area and the solvation energy difference between aqueous and solvent phases. Next, an application of log P in QSAR analyses of ligand-CYP (Cytochrome P450) interaction was described. Azole compounds are widely used as antifungal agents. We showed that the binding affinity of 18 azole compounds with CYP2B and CYP3A were nicely expressed by the bilinear model of log P. These results suggest that molecular hydrophobicity plays a major role in the binding affinity. The binding mechanism was discussed based on the correlation equations.

¹Presented at CMTPI 2007: Computational Methods in Toxicology and Pharmacology Integrating Internet Resources (Moscow, Russia, September 1–5, 2007).

Keywords:

• ab initio MO
• accessible surface area
• azole
• bilinear model
• CYP
• self consistent reaction field

Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and the Technology of Japan Science and Technology Corporation (JST-CREST), and the 21st Century COE Program, Human Nutritional Science on Stress Control, Tokushima, Japan.

Notes

¹Presented at CMTPI 2007: Computational Methods in Toxicology and Pharmacology Integrating Internet Resources (Moscow, Russia, September 1–5, 2007).