1TA2

Crystal structure of thrombin in complex with compound 1

Summary for 1TA2

• Entry DOI: 10.2210/pdb1ta2/pdb
• Related: 1SL3 1TA6
• Descriptor: thrombin, Hirudin, 1-(2-AMINO-3,3-DIPHENYL-PROPIONYL)-PYRROLIDINE-3-CARBOXYLIC ACID 2,5-DICHLORO-BENZYLAMIDE, ... (4 entities in total)
• Functional Keywords: thrombin inhibitor complex, blood clotting, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space: P00734; Secreted: P28504
• Total number of polymer chains: 2
• Total formula weight: 34952.83

Authors

Tucker, T.J.,Brady, S.F.,Lumma, W.C.,Lewis, S.D.,Gardel, S.J.,Naylor-Olsen, A.M.,Yan, Y.,Sisko, J.T.,Stauffer, K.J.,Lucas, B.Y.,Lynch, J.J.,Cook, J.J.,Stranieri, M.T.,Holahan, M.A.,Lyle, E.A.,Baskin, E.P.,Chen, I.-W.,Dancheck, K.B.,Krueger, J.A.,Cooper, C.M.,Vacca, J.P. (deposition date: 2004-05-19, release date: 2004-06-08, Last modification date: 2024-11-20)

Primary citation

Tucker, T.J.,Brady, S.F.,Lumma, W.C.,Lewis, S.D.,Gardel, S.J.,Naylor-Olsen, A.M.,Yan, Y.,Sisko, J.T.,Stauffer, K.J.,Lucas, B.Y.,Lynch, J.J.,Cook, J.J.,Stranieri, M.T.,Holahan, M.A.,Lyle, E.A.,Baskin, E.P.,Chen, I.-W.,Dancheck, K.B.,Krueger, J.A.,Cooper, C.M.,Vacca, J.P.
Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position
J.Med.Chem., 41:3210-3219, 1998

PubMed Abstract: As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

PubMed: 9703466
DOI: 10.1021/jm9801713

Experimental method

X-RAY DIFFRACTION (2.3 Å)