A Critical Review of Recent CoMFA Applications

Abstract

Comparative molecular field analysis (CoMFA) is a technique for determining threedimensional quantitative structure‐activity relationships (3D QSAR). In a standard CoMFA procedure, a bioactive conformation of each compound under study is chosen, and all the structures are superimposed in a manner defined by the supposed mode of interaction with the target macromolecule. Then, the steric and the electrostatic fields of these molecules are calculated with a probe atom, such as sp 3 carbon atom with +1 charge, at regularly spaced (1 or 2 A) points of a three-dimensional grid. Sometimes other fields or physico-chemical parameters are also included. The calculated energy values and other descriptor values are then analyzed with the partial least-squares (PLS) statistical technique. The optimum number of components for the CoMFA model is selected based on the cross-validation test results. The final CoMFA model is derived using the optimum number of components selected. The results are usually displayed as coefficient contour maps. A good CoMFA model should show satisfactory statistical significance, explanatory capability of the variance in the activity of the compounds in the training set and predictive power of the potency of new compounds. This work describes the CoMFA studies published since 1993. Any aspects of the standard CoMFA procedure or the works described in the previous volume [156L] * of this book or those subjects that are extensively discussed in other chapters of this volume are not discussed in any detail. For such subjects, readers are referred to the corresponding chapters in this volume. There are many choices to be considered in a CoMFA analysis: [134L] biological data, selection of compounds and series design, generation of three-dimensional structure and charges of the ligand molecules, conformational analysis and establishment of the bioactive conformation of each molecule, alignment of the molecules, position of the lattice points, choice of force fields and calculation of the interaction energies, statistical analysis of the data and the selection of the final model, display of the results in contour maps and their interpretations, and design and forecasting the activity of unknown compounds. Those studies reported in the last few years can be largely divided into two groups. The first group includes those that studied various aspects of CoMFA procedures to