The use of 3D structural data in the design of specific factor Xa inhibitors

Factor Xa (fXa) is a serine protease that plays a critical role in the blood coagulation process and qualifies as an attractive target for finding new antithrombotics. In the case of fXa several structure based drug design strategies have been followed because of the difficulty in growing fXa co-crystals routinely. This has led to the use of surrogate proteins such as trypsin. Factor Xa inhibitors for which the binding mode has been determined experimentally or modeled are described in this review. The inhibitors are divided into three fragments: a P1 group, a central scaffold and a P4 group. In this review, interactions in each sub-site of fXa with various inhibitor fragments have been examined at the molecular level and were shown to bind, in most cases, independently of the rest of the molecule. Knowledge of the 3D structure of the binding mode of ligands to target proteins has been successfully applied in designing fXa inhibitors with enhanced specificity, affinity and has provided hints to modulate the physico-chemical properties of the small molecule ligand.