Quantitative comparison of molecular electrostatic potentials for structure‐activity studies

Abstract An approach for representing, efficiently calculating and comparing discrete three‐dimensional molecular electrostatic potentials using a quantitative similarity index (MEP‐SI) based on a Carbo‐type formalism is presented. A radial‐type (MACRA) grid representation is described that provides more efficient storage of MEP information than a cubic grid of similar range, appropriate emphasis, and a convenient means for restricting the comparison of MEP functions to a local molecule region. The MACRA based MEP‐SI formalism was used to evaluate the suitability of a variety of approximate methods for efficiently calculating the MEP for use in MEP‐SI comparison of dissimilar molecules. The Mulliken charge method was found inadequate, while the method of potential‐derived charges (PDCs), with additional charges for lone electron pairs included on sulfur, provided an efficient and sufficiently accurate representation of the MEP for this purpose. Convergence of the MEP‐SI with respect to MACRA grid extent and mesh size was demonstrated; the effect of MEP error and different grid point emphasis in the MACRA versus the cubic grid results was investigated, and MEP‐SI results were compared for different forms of the SI equation. The methodology proposed in this study provides an efficient and practical means for comparing MEP functions for two molecules and gives discriminating results for a sample series of molecular analogues consistent with expectations.