CORRELATION OF BINDING AFFINITIES WITH NONBONDED INTERACTION ENERGIESOF THROMBIN-INHIBITOR COMPLEXES

Several empirical modeling protocols are evaluated allowing a quantifi cation of the interaction between an enzyme and a series of inhibitors . The evaluation and optimization of the modeling protocols used a dat abase of 35 non-covalently bound inhibitors of human thrombin. Intermo lecular interaction energies were calculated with CHARMm after energy minimization of the modeled complexes using various dielectric functio ns and constraining strategies. These calculated binding energies were correlated with the experimentally obtained binding constants of the inhibitors. The best protocols resulted in linear correlations with co rrelation coefficients > 0.80. In the best protocols the enzyme was fu lly constrained, the ligand was allowed to move freely and electrostat ics were scaled down drastically or fully neglected during the energy minimization. For the interaction energy evaluation step, a distance-d ependent dielectric function epsilon = R proved to be optimal. This si mple empirical protocol, that neglects solvation or entropy effects, c an be implemented readily in other force field packages and may be app lied on various enzyme-inhibitor complexes, providing a tool for the e valuation and rank-ordering of newly designed inhibitors.