Crystal structures of human factor Xa complexed with potent inhibitors

Involved in the coagulation cascade, factor Xa (FXa) is a serine protease w hich has received great interest as a potential target for the development of new antithrombotics. Although there is a great wealth of structural data on thrombin complexes, few structures of ligand/FXa complexes have been re ported, presumably because of the difficulty in growing crystals. Reproduci ble crystallization conditions for human des-Gla1-45 coagulation FXa have b een found. This has led to an improvement in the diffraction quality of the crystals (about 2.1 Angstrom) when compared to the previously reported for ms (2.3-2.8 Angstrom) thus providing a suitable platform for a structure-ba sed drug design approach. A series of crystal structures of noncovalent inh ibitors complexed with FXa have been determined, three of which are present ed herein. These include compounds containing the benzamidine moiety and su rrogates of the basic group. The benzamidine-containing compound binds in a canonical fashion typical of synthetic serine protease inhibitors. On the contrary, molecules that contain surrogates of the benzamidine group do not make direct hydrogen-bonding interactions with the carboxylate of Asp189 a t the bottom of the S1 pocket. The structural data provide a likely explana tion for the specificity of these inhibitors and a great aid in the design of bioavailable potent FXa inhibitors.