The use of molecular electrostatic potentials as hydrogen-bonding-donor parameters for QSAR studies

Abstract

Hydrogen bonding is an important interaction, which controls solubility, partitioning and transport of drugs and is an important force in drug-receptor interactions. Unfortunately it is difficult to quantify, and so inclusion of hydrogen bonding descriptors into quantitative structure-activity relationships (QSARs) is often restricted to indicator variables. The prime objective of this work was to devise readily accessible hydrogen bonding descriptors by means of theoretical chemistry to use in QSAR studies. Because of the dominantly electrostatic nature of this bond, molecular-electrostatic potential was considered and the highest electrostatic potential on the solvent accessible surface (ESP +) was used as the hydrogen-bonding-donor ability of the molecule. The ability of this descriptor to predict the measured hydrogen bonding parameter of ∑α H 2 was compared with that of the empirically derived atomic charges. The efficiency of ESP + in a QSAR was also examined. The results suggested that ESP + was superior to the atomic charge descriptor and that the use of this parameter as the hydrogen bonding parameter in QSAR studies was successful.