Estimation of binding affinities for selective thrombin inhibitors via Monte Carlo simulations

Monte Carlo simulations have been performed on a series of 20 active-site-d irected thrombin inhibitors to determine the interactions and energetics as sociated with the binding of these compounds. Physicochemical descriptors o f potential value in the prediction of binding affinities were averaged dur ing simulations of each inhibitor unbound in water and bound to thrombin. R egression equations based on 3-5 descriptors are able to reproduce the expe rimental binding affinities, which cover a 7 kcal/mol range, with rms error s of 1.0-1.3 kcal/mol, and yield correlation coefficients, r(2), Of 0.7-0.8 . On the basis of these results, the quantities most important in determini ng the binding affinities are: (1) the enhancement of van der Waals interac tions in going from solution to the bound state, (2) the intramolecular str ain induced in the inhibitor upon binding, (3) the number of hydrogen bonds lost in the binding process, and (4) the number of rotatable bonds in the inhibitor. The descriptors are physically reasonable and, in combination wi th the insights gained from analysis of the simulation structures, suggest directions for the development of improved thrombin inhibitors.