SCORE: A new empirical method for estimating the binding affinity of a protein-ligand complex

A new method is presented to estimate the binding affinity of a protein-lig and complex with known three-dimensional structure. The method, SCORE, uses an empirical scoring function to describe the binding free energy, which i ncludes terms to account for van der Waals contact, metal-ligand bonding, h ydrogen bonding, desolvation effect, and deformation penalty upon the bindi ng process. The coefficients of each term are obtained by multivariate regr essional analysis of a diverse training set of 170 protein-ligand complexes . The final scoring function reproduces the binding free energies of the wh ole training set with a cross-validated deviation of 6.3 kJ/mol. The predic tive ability of the function is further tested by a set of 11 endothiapepsi n complexes and the internal consistency of the function is demonstrated in a stepwise procedure named Evolutionary Test. A major innovation of this m ethod is the introduction of an atomic binding score which allows the resea rcher to inspect and optimize the lead compound rationally in a structure-b ased drug design scheme.