1Z71

thrombin and P2 pyridine N-oxide inhibitor complex structure

Summary for 1Z71

• Entry DOI: 10.2210/pdb1z71/pdb
• Descriptor: thrombin, Hirudin IIIB', L17, ... (4 entities in total)
• Functional Keywords: thrombin inhibitor complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space: P00734; Secreted: P28511
• Total number of polymer chains: 2
• Total formula weight: 35011.76

Authors

Nantermet, P.G.,Burgey, C.S.,Robinson, K.A.,Pellicore, J.M.,Newton, C.L.,Deng, J.Z.,Lyle, T.A.,Selnick, H.G.,Lewis, S.D.,Lucas, B.J.,Krueger, J.A.,Miller-Stein, C.,White, R.B.,Wong, B.,McMasters, D.R.,Wallace, A.A.,Lynch Jr., J.J.,Yan, Y.,Chen, Z.,Kuo, L.,Gardell, S.J.,Shafer, J.A.,Vacca, J.P. (deposition date: 2005-03-23, release date: 2005-05-17, Last modification date: 2024-10-16)

Primary citation

Nantermet, P.G.,Burgey, C.S.,Robinson, K.A.,Pellicore, J.M.,Newton, C.L.,Deng, J.Z.,Selnick, H.G.,Lewis, S.D.,Lucas, B.J.,Krueger, J.A.,Miller-Stein, C.,White, R.B.,Wong, B.,McMasters, D.R.,Wallace, A.A.,Lynch Jr., J.J.,Yan, Y.,Chen, Z.,Kuo, L.,Gardell, S.J.,Shafer, J.A.,Vacca, J.P.,Lyle, T.A.
P(2) pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold
BIOORG.MED.CHEM.LETT., 15:2771-2775, 2005

PubMed Abstract: In this study, we have demonstrated that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core is more resistant toward oxidative metabolism, it also overcomes the metabolic liability associated with the pyrazinones. An optimization study of the P(1) benzylamide delivered the potent thrombin inhibitor 21 (K(i) = 3.2 nM, 2xaPTT = 360 nM), which exhibited good plasma levels and half-life after oral dosing in the dog (C(max) = 2.6 microM, t(1/2) = 4.5 h).

PubMed: 15911253
DOI: 10.1016/j.bmcl.2005.03.110

Experimental method

X-RAY DIFFRACTION (1.8 Å)