Computational modelling of inhibitor binding to human thrombin

Thrombin is an essential protein involved in blood clot formation and an im portant clinical target, since disturbances of the coagulation process caus e serious cardiovascular diseases such as thrombosis. Here we evaluate the performance of a molecular dynamics based method for predicting the binding affinities of different types of human thrombin inhibitors. Far a series o f eight ligands the method ranks their relative affinities reasonably well. The binding free energy difference between high and low affinity represent atives in the test set is quantitatively reproduced, as well as the stereos pecificity for a chiral inhibitor. The original parametrisation of this lin ear interaction energy method requires the addition of a constant energy te rm in the case of thrombin. This yields a mean unsigned error of 0.68 kcal/ mol for the absolute binding free energies. This type of approach is also u seful for elucidating three-dimensional structure-activity relationships in terms of microscopic interactions of the ligands with the solvated enzyme. (C) 2001 Elsevier Science BN. All rights reserved.