Factor Xa: Simulation studies with an eye to inhibitor design

Factor Xa is a serine protease which activates thrombin and plays a key reg ulatory role in the blood-coagulation cascade. Factor Xa is at the crossroa ds of the extrinsic and intrinsic pathways of coagulation and, hence, has b ecome an important target for the design of anti-thrombotics (inhibitors). It is not known to be involved in other processes than hemostasis and its b inding site is different to that of other serine proteases, thus facilitati ng selective inhibition. The design of high-affinity selective inhibitors o f factor Xa requires knowledge of the structural and dynamical characterist ics of its active site. The three-dimensional structure of factor Xa was re solved by X-ray crystallography and refined at 2.2 Angstrom resolution by P admanabhan and collaborators. In this article we present results from molec ular dynamics simulations of the catalytic domain of factor Xa in aqueous s olution. The simulations were performed to characterise the mobility and fl exibility of the residues delimiting the unoccupied binding site of the enz yme, and to determine hydrogen bonding propensities (with protein and with solvent atoms) of those residues in the active site that could interact wit h a substrate or a potential inhibitor. The simulation data is aimed at fac ilitating the design of high-affinity selective inhibitors of factor Xa.