Use of the Supermolecule Approach to Derive Molecular Similarity Descriptors for QSAR Analysis

Abstract

A relevant aspect in quantitative structure-activity (QSAR) and structure-selectivity (QSSR) relationships studies is the choice of the most appropriate molecular descriptors both with respect to the molecular series considered and the known or hypothetical mechanism of drug action. We have recently shown that ad hoc derived size and shape descriptors have been successful to derive QSAR and QSSR models for α1-adrenergic antagonists, 5-HT1A serotoninergic receptor ligands and M1 muscarinic ligands, especially when dealing with non congeneric series of molecules. These descriptors describe the size-shape similarity with respect to a reference supermolecule which is obtained by superposition of the most active (selective) and structural different compounds, better if rigids. Molecular similarity indices based on molecular electrostatic potential (MEP) have found, as well, widespread use in the QSAR area.