crystal structure ¥ drug research ¥ Factor Xa ¥ induced fit ¥ inhibitors Advances in the various genome sequencing projects promise to provide fresh impetus to the target-oriented search for novel drugs to treat human ailments. [1] Crucial to this pursuit is the fast and efficient identification and optimization of new lead compounds. Current approaches to identification rely heavily on high-throughput screening and increasingly on virtual computer screening. Optimization is driven largely by chemical intuition complemented by the translation of structural constraints (for example, pharmacophore patterns) into molecular skeletons. Typical compounds arising from experimental screening exhibit binding constants of the order of 10 À5 M with respect to their target receptors or enzymes. To further develop any hits, it is necessary to coordinate the experimental binding data with chemical features of the ensemble of ligands found to be responsible and determinant for receptor binding. Thus, a frequent assumption for lead development is that the hits found by screening can be associated with a definitive binding mode common to all inhibitors (pharmacophore hypothesis). Here we explore the link between affinity and binding mode and the extent to which lead development might be influenced by choice of experimental system.
We investigated the structural requirements for the inhibition of Factor Xa, a serine protease involved in blood clotting. [2±4] Most synthetic inhibitors for this enzyme contain a basic group that binds in the primary specificity (S1) pocket, although such moieties are generally detrimental to oral uptake and systemic bioavailability. [5] Zeneca have patented a series of Factor Xa inhibitors [6] that contain a weakly basic pyridine group such as that in 1 (Scheme 1). We investigated the interaction of 1 with the archaetypal serine proteinase trypsin to try to understand how 1 inhibits Factor Xa. Compound 1 inhibits bovine b-trypsin Scheme 1. Chemical formulae of two Factor Xa inhibitors for which structural data are available: compound 1 (Zeneca) the subject of this investigation; compound 2 (Daiichi) DX9065a.