Development of molecular hydrogen-bonding potentials (MHBPs) and their application to structure-permeation relations.

Abstract

This study describes the construction of Molecular Hydrogen-Bonding Potentials (MHBPs), a computational tool designed to characterize three-dimensional hydrogen-bonding properties of molecules. The methodology follows a stepwise approach analogous to that used for Molecular Lipophilicity Potential (MLP) generation. A fragmental system was derived from solvatochromic parameters, assigning donor fragment values (alpha) to polar hydrogen atoms and acceptor fragment values (beta) to polar heavy atoms. Distance and angle functions were incorporated to account for spatial variation of hydrogen-bonding interactions. MHBPs were computed on molecular surfaces and three-dimensional grids. Validation against GRID interaction energies and correlation with oral drug absorption data confirmed the utility of MHBPs. The tool shows promise for drug design applications, with ongoing integration into CoMFA and VolSurf frameworks.

Mechanism

Donor (alpha) and acceptor (beta) fragment values derived from solvatochromic parameters are combined with distance and angle functions to compute hydrogen-bonding potentials across molecular surfaces in three dimensions.