Comparison of electrostatic similarity approaches applied to a series of ketanserin analogues with 5-HT2A antagonistic activity

Abstract

Similarities between the molecular electrostatic potential (MEP) distributions of a series of analogues of ketanserin were studied using the MEPSIM package with the aim of correlating MEP patterns with the binding affinities for the 5-HT2A receptor. This study was also used to assess different approaches that can be used in this kind of similarity studies. The best correlation between MEP distributions and biological activities was found when only negative electrostatic potentials were taken into account, while the consideration of the whole MEP distribution produced a classification of the compounds than was mainly steric and not related with their biological activities. The two structural features of the considered molecules that generated negative MEP zones and consequently that could be related with their recognition by the 5-HT2A receptor, were the lone pairs of a carbonyl oxygen and the π-system of an aromatic ring.