INTERRELATION BETWEEN ELECTROSTATIC AND LIPOPHILICITY POTENTIALS ON MOLECULAR-SURFACES

Molecular electrostatics and lipophilicity are two important propertie s included in quantitative structure-activity relationships (QSARs) em ployed for rational drug design. The molecular electrostatic potential (MEP) provides information on the position, distribution, and extent of electrophilic and nucleophilic regions around a molecule. Similarly , the solvent affinity can be represented by a local phenomenological potential of semiempirical nature: the molecular lipophilicity potenti al (MLP). Although a simultaneous, three-dimensional display of MEP an d MLP is possible, it may not provide a practical tool for comparing m olecules. In this work, we deal with the simpler two-dimensional maps of the entire molecular surface projected onto an MEP-MLP plane. We an alyze how these maps change with the following factors: (1) compositio n and molecular geometry, (2) the quality of the computation of MEP, a nd (3) the parameter set used for evaluating the lipophilicity potenti al. The approach is used to compare series of pyrazole derivatives. Th e methodology is useful in assessing molecular similarity, as well as in establishing the nature of differences between compounds.