Abstract
The quantum chemical and structure‐based technique heuristic molecular lipophilicity potential (HMLP) is used in the liver alcohol dehydrogenase (LADH) study of molecular family pyrazole and derivatives. The molecular lipophilic index L~M~, molecular hydrophilic index H~M~, lipophilic indices l~s~s, and hydrophilic indices h~s~s of the substitutes (fragments), and atomic lipophilicity indices l~a~s are constructed and used in QSAR study. The HMLP indices are correlated with bioactivities of 18 pyrazole derivatives according to the 2D QSAR procedure. The multiple linear regression equation between the bioactivities of pyrazole derivatives and HMLP indices are built using partial least square (PLS) with the optimal statistical quantity (r = 0.987, s = 0.479, F = 47.19). The inhibition mechanism of LADH of the pyrazole derivatives is explained according to the physical meaning of HMLP indices. During the HMLP calculations for the 2D QSAR, the only input parameters are the atomic van der Waals radius without the need to resort to any empirical parameters. Accordingly, HMLP can provide a rigorous theoretical approach with a crystal clear physical meaning for the 2D QSAR. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 461–470, 2005