Molecular shape analysis for quantitative drug design

ABSTRACT

One of the goals of the rational drug design using quantitative structure-activity relationship [QSAR]' is to derive a relationship between some numerical expression of the structures of compounds and their activity. The objective is to predict the structure[s] of more active compounds. The pioneering work of Hansch el at. provided a formula for deriving QSARs, which could be used to predict activity from structure. A major limitation of this approach is that its descriptors are derived from 2-dimensional structures. Comparative molecular field analysis, CoMFA, molecular shape analysis, MSA, distance geometry, and molecular matrices are four methods which explicitly treat the 3-dimensional structure of the ligand and thus yield 3-dimensional quantitative structure-activity relationships, 3D-QSARs. The present article will review the molecular shape analysis MSA, as one of the most valuable 3D-QSAR method. MSA seeks the active conformation of a molecule, expresses molecular shape similarity in terms of a variety of scalar descriptors, such as common overlap steric volume Vo [COSV], measured relative to some reference compound and conformation, and permits the use of other common 2- and 3-dimensional descriptors in the development of structure-activity models