5K0H

Human factor Xa in complex with synthetic inhibitor benzylsulfonyl-dSer(Benzyl)-Gly-4-amidinobenzylamide

Summary for 5K0H

• Entry DOI: 10.2210/pdb5k0h/pdb
• Descriptor: Coagulation factor X, CALCIUM ION, O-benzyl-N-(benzylsulfonyl)-D-seryl-N-[(4-carbamimidoylphenyl)methyl]glycinamide, ... (5 entities in total)
• Functional Keywords: human factor xa, inhibitor complex, benzamidine inhibitor, hydrolase, clotting factor
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: P00742 P00742
• Total number of polymer chains: 2
• Total formula weight: 32524.95

Authors

Steinmetzer, T. (deposition date: 2016-05-17, release date: 2016-07-06, Last modification date: 2024-11-06)

Primary citation

Schweinitz, A.,Sturzebecher, A.,Sturzebecher, U.,Schuster, O.,Sturzebecher, J.,Steinmetzer, T.
New substrate analogue inhibitors of factor Xa containing 4-amidinobenzylamide as P1 residue: part 1.
Medicinal Chemistry, 2:349-361, 2006

PubMed Abstract: The trypsin-like serine protease factor Xa (fXa) is located at the convergence point of the intrinsic and extrinsic coagulation cascade, and therefore has emerged as an attractive target for the design of novel anticoagulants. During the development of substrate-analogue urokinase inhibitors we have found that the protection of the P3-dSer side chain leads to a scaffold of potent fXa inhibitors with the general structure R1-SO2-dSer(R2)-Gly-4-amidinobenzylamide. The first lead (3) with an N-terminal benzylsulfonyl group and dSer(tBu) as P3 residue inhibits human fXa with a Ki of 14 nM. A variety of derivatives with modified P4, P3, and P2 residues have been investigated in terms of inhibition of fXa and related proteases and for their anticoagulant potency and elimination behaviour. Most inhibitors were rapidly cleared from the circulation of rats. However, compound 48 (Ki= 3.5 nM), one of the most potent and selective inhibitors containing a dArg as P3 residue was relatively slowly eliminated (t1/2 approximately 1 h). Inhibitor 48 doubled clotting times in human plasma at 0.32 microM (aPTT) and 0.28 microM (PT), and is approximately 10-fold more potent than the reference fXa inhibitor DX-9065a in the inhibition of the prothrombinase complex. The structures of two inhibitors in complex with human fXa were solved by X-ray crystallography.

PubMed: 16848746
DOI: 10.2174/157340606777724040

Experimental method

X-RAY DIFFRACTION (2.2 Å)