PDBsum entry 2feq

Hydrolase/hydrolase inhibitor

PDB id: 2feq

Contents

Protein chains

28 a.a. *

250 a.a. *

11 a.a. *

Ligands

34P

Waters ×100

* Residue conservation analysis

PDB id:

2feq

Name:

Hydrolase/hydrolase inhibitor

Title:

Orally active thrombin inhibitors

Structure:

Thrombin light chain. Chain: l. Thrombin heavy chain. Chain: h. Decapeptide hirudin analogue. Chain: d. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Synthetic: yes. Synthetic. Other_details: deduced from c-terminus of hirudin

Biol. unit:

Trimer (from PQS)

Resolution:

2.44Å R-factor: 0.185 R-free: 0.242

Authors:

H.Mack,D.Baucke,W.Hornberger,U.E.W.Lange,H.W.Hoeffken

Key ref:

H.Mack et al. (2006). Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety. Bioorg Med Chem Lett, 16, 2641-2647. PubMed id: 16517159 DOI: 10.1016/j.bmcl.2006.02.040

Date:

16-Dec-05 Release date: 08-Aug-06

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 28 a.a.

Protein chain

P00734  (THRB_HUMAN) -  Prothrombin from Homo sapiens

Seq: 622 a.a.

Struc: 250 a.a.

Protein chain

No UniProt id for this chain

Struc: 11 a.a.

Enzyme reactions

• Enzyme class: Chains L, H: E.C.3.4.21.5 - thrombin.
• Reaction: Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.

DOI no: 10.1016/j.bmcl.2006.02.040

Bioorg Med Chem Lett 16:2641-2647 (2006)

PubMed id: 16517159

Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety.

H.Mack, D.Baucke, W.Hornberger, U.E.Lange, W.Seitz, H.W.Höffken.

ABSTRACT

The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH(2)-d-cyclohexylalanyl-3,4-dehydroprolyl-NH-CH(2)-aryl-C(=NH)NH(2) are described together with their ecarin clotting time (ECT) prolongation as measure for thrombin inhibition ex vivo. The aryl P1-moiety mimicking the arginine part of the d-Phe-Pro-Arg derived thrombin inhibitors turned out to be a key component for in vitro potency and in vivo activity. Optimization of this part led to compounds with improved antithrombin activity in rats and dogs after oral administration compared to the recently launched anticoagulant melagatran.