Journal of Computer-Aided Molecular Design, 5 (1991) 545-552 545 ESCOM J-CAMD 141 HINT: A new method of empirical hydrophobic field calculation for CoMFA Glen E. Kellogg*, Simon F. Semus and Donald J. Abraham Department of Medicinal Chemistry and Division of Biomedical Engineering, Medical College of Virgmia, Virginia Commonwealth University, Richmond, VA 23298-0540, U.S.A. Received 8 December 1990 Accepted 2 July 1991 Key words: Comparative Molecular Field Analysis; HINT; Hydrophobicity; Hydrophobic atom constant; PLS SUMMARY An empirical hydrophobic field-like 3D function has been calculated with the program HINT (hydro- phobic interactions) and imported into the SYBYL implementation of CoMFA (Comparative Molecular Field Analysis). The addition of hydrophobicity appears to offer increased chemical interpretability of CoMFA models. An example is given using the steroid model reported by Cramer et al. (J. Am. Chem. Soc., 110 (1988) 5959). While addition of the HINT field did not improve statistical parameters in this model, the CoMFA coefficient contours from the hydrophobic field unambiguously define the most active steroid mole- cules in the chemical terms of hydrophobic and polar substituents. INTRODUCTION In the short time since the Comparative Molecular Field Analysis (CoMFA) was initially de- scribed by Cramer et al. [1], the method has become a popular and valuable tool for computer- aided drug design [2-5]. The standard CoMFA method samples steric and electrostatic fields sur- rounding a set of drugs/ligands to determine a quantitative structure-activity relationship (QSAR). To address the importance of hydrophobicity in QSAR, we have integrated an empirical hydrophobic field into CoMFA and show that for drug-design purposes the three-field analysis may have improved predictive and interpretive capabilities over the standard two-field analysis. Steroid binding to corticosteroid-binding globulin is used to illustrate the technique. Hydrophobicity has long been regarded as a key parameter for understanding drug activity [6,7]. Practically, hydrophobicity is measured and reported as P, the partition coefficient of solu- bility between water and an organic solvent. Hansch first demonstrated the use of log P and sub- * To whom correspondence should be addressed. 0920-654X/$ 5.00 © 1991 ESCOM Science Publishers B.V.