Contribution of Explicit Solvent Effects to the Binding Affinity of Small‐Molecule Inhibitors in Blood Coagulation Factor Serine Proteases

The prevention of blood coagulation is important in treating thromboembolic disorders, and several serine proteases involved in the coagulation cascade have been classified as pharmaceutically relevant. Whereas structure‐based drug design has contributed to the development of some serine protease inhibitors, traditional computational methods have not been able to fully describe structure–activity relationships (SAR). Here, we study the SAR for a number of serine proteases by using a method that calculates the thermodynamic properties (enthalpy and entropy) of the water that solvates the active site. We show that the displacement of water from specific subpockets (such as S1–4 and the ester binding pocket) of the active site by the ligand can govern potency, especially for cases in which small chemical changes (i.e., a methyl group or halogen) result in a substantial increase in potency. Furthermore, we describe how relative binding free energies can be estimated by combining the water displacement energy with complementary terms from an implicit solvent molecular mechanics description binding.