title: Thrombin inhibitor design: X-ray and solution studies provide a novel P1 determinant.
abstract: The crystal structures of proflavin and 6-fluorotryptamine thrombin have been completed showing binding of both ligands at the active site S1 pocket. The structure of proflavin:thrombin was confirmatory, while the structure of 6-fluorotryptamine indicated a novel binding mode at the thrombin active site. Furthermore, speculation that the sodium atom identified in an extended solvent channel beneath the S pocket may play a role in binding of these ligands was investigated by direct proflavin titrations as well as chromogenic activity measurements as a function of sodium concentration at constant ionic strength. These results suggested a linkage between the sodium site and the S1 pocket. This observation could be due to a simple ionic interaction between Asp189 and the sodium ion or a more complicated structural rearrangement of the thrombin S1 pocket. Finally, the unique binding mode of 6-fluorotryptamine provides ideas toward the design of a neutrally charged thrombin inhibitor.
authors.affiliation: Department of Chemical and Physical Sciences, DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880, USA.
authors.forename: V L
authors.initials: VL
authors.lastname: Nienaber
authors.forename: P D
authors.initials: PD
authors.lastname: Boxrud
authors.forename: L J
authors.initials: LJ
authors.lastname: Berliner
mesh_terms: D000991:Antithrombins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D007700:Kinetics; D011370:Proflavine / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D012996:Solutions; D014363:Tryptamines / Q000737:chemistry
chemical_list: D000991:Antithrombins; D012996:Solutions; D014363:Tryptamines; C030820:tryptamine; D011370:Proflavine