The use of atomic charges and orbital energies as hydrogen-bonding-donor parameters for QSAR studies: comparison of MNDO, AM1 and PM3 methods.

Hydrogen-bonding, important in drug-receptor interactions, also determines the solubility and partitioning of drugs between phases. It is, therefore, important to incorporate the effects of hydrogen-bonding in studies of quantitative structure-activity relationships (QSAR). In this study the atomic charge on the most positively charged hydrogen atom in a molecule and the energy of the lowest unoccupied molecular orbital (LUMO) have been used as a measure of hydrogen-bond-donor capacity. For several hydrogen-bonding acids the Mulliken atomic charges and the energy of the LUMO produced by use of three semiempirical methods, AM1, PM3 and MNDO, and MNDO electrostatic-potential-derived atomic charges, have been compared in correlations with solvatochromic hydrogen-bonding acidity (sigmaalpha(H)2). Atomic charges and LUMO energies, particularly those calculated by use of the AM1 and MNDO methods, were found to correlate well with sigmaalpha(H)2. They were also found to be good models of hydrogen-bonding in QSAR correlations.