PREDICTION OF DRUG-BINDING AFFINITIES BY COMPARATIVE BINDING-ENERGY ANALYSIS

A new computational method for deducing quantitative structure-activit y relationships (QSARs) using structural data from ligand-macromolecul e complexes is presented. First, the ligand-macromolecule interaction energy is computed for a set of ligands using molecular mechanics calc ulations. Then, by selecting and scaling components of the ligand-macr omolecule interaction energy that show good predictive ability, a regr ession equation is obtained in which activity is correlated with the i nteraction energies of parts of the Ligands and key regions of the mac romolecule. Application to the interaction of the human synovial fluid phospholipase A(2) with 26 inhibitors indicates that the derived QSAR has good predictive ability and provides insight into the mechanism o f enzyme inhibition. The method, which we term comparative binding ene rgy (COMBINE) analysis, is expected to be applicable to ligand-recepto r interactions in a range of contexts including rational drug design, host-guest systems, and protein engineering.