caa a22 4500 475744292 CHVBK 20180406123508.0 cr unu---uuuuu 170329e20000501xx s 000 0 eng 10.1023/A:1007055615190 doi (NATIONALLICENCE)springer-10.1023/A:1007055615190 Thrombin Inhibitor Design: X-Ray and Solution Studies Provide a Novel P1 Determinant [Elektronische Daten] [Vicki Nienaber, Paul Boxrud, Lawrence Berliner] 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 S1 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. Plenum Publishing Corporation, 2000 Proflavin nationallicence 6-fluorotryptamine nationallicence thrombin nationallicence X-ray crystallography nationallicence serine protease nationallicence Nienaber Vicki Department of Chemical and Physical Sciences, DuPont Merck Pharmaceutical Company, Experimental Station, 19880, Wilmington, Delaware aut Boxrud Paul Department of Chemical and Physical Sciences, DuPont Merck Pharmaceutical Company, Experimental Station, 19880, Wilmington, Delaware aut Berliner Lawrence Department of Chemical and Physical Sciences, DuPont Merck Pharmaceutical Company, Experimental Station, 19880, Wilmington, Delaware aut Journal of Protein Chemistry Kluwer Academic Publishers-Plenum Publishers 19/4(2000-05-01), 327-333 0277-8033 19:4<327 2000 19 10930 https://doi.org/10.1023/A:1007055615190 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1007055615190 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Nienaber Vicki Department of Chemical and Physical Sciences, DuPont Merck Pharmaceutical Company, Experimental Station, 19880, Wilmington, Delaware aut NATIONALLICENCE 700 1- Boxrud Paul Department of Chemical and Physical Sciences, DuPont Merck Pharmaceutical Company, Experimental Station, 19880, Wilmington, Delaware aut NATIONALLICENCE 700 1- Berliner Lawrence Department of Chemical and Physical Sciences, DuPont Merck Pharmaceutical Company, Experimental Station, 19880, Wilmington, Delaware aut NATIONALLICENCE 773 0- Journal of Protein Chemistry Kluwer Academic Publishers-Plenum Publishers 19/4(2000-05-01), 327-333 0277-8033 19:4<327 2000 19 10930 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer