Estimation of molecular similarity based on 4D-QSAR analysis: Formalism and validation

The 4D-QSAR paradigm has been used to develop a formalism to estimate molec ular similarity measures as a function of conformation, alignment, and atom type. It is possible to estimate the molecular similarity of pairs of mole cules based upon the entire ensemble of conformational states each molecule can adopt at a given temperature, normally room temperature. Molecular sim ilarity can be measured in terms of the types of atoms composing each molec ule leading to multiple measures of molecular similarity. Multiple measures of molecular similarity can also arise from using different alignment rule s to perform relative molecular similarity, RMS, analysis. An alignment ind ependent method of determining molecular similarity measures, referred to a s absolute molecular similarity, AMS, analysis has been developed. Various sets and libraries of compounds, including the amino acids, are analyzed us ing 4D-QSAR molecular similarity analysis to demonstrate the features of th e formalism. Exploration of molecular similarity as a function of chirality , identification of common embedded 3D pharmacophores in compounds, and elu cidation of 3D-isosteric compounds from structurally diverse libraries are carried out in the application studies.