PDBsum entry 2bmg

Hydrolase

PDB id: 2bmg

Contents

Protein chains

53 a.a. *

234 a.a. *

Ligands

I1H

Metals

_CA

Waters ×218

* Residue conservation analysis

PDB id:

2bmg

Name:

Hydrolase

Title:

Crystal structure of factor xa in complex with 50

Structure:

Coagulation factor x. Chain: a. Fragment: light chain, residues 126-178. Synonym: blood coagulation factor xa, stuart factor, stuart-prower factor. Coagulation factor x. Chain: b. Fragment: heavy chain, residues 235-468. Synonym: blood coagulation factor xa, stuart factor, stuart-prower

Source:

Homo sapiens. Human. Organism_taxid: 9606. Tissue: blood. Tissue: blood

Biol. unit:

Dimer (from PDB file)

Resolution:

2.70Å R-factor: 0.193 R-free: 0.277

Authors:

H.Schreuder,H.Matter,D.W.Will,M.Nazare,V.Laux,V.Wehner,P.Loenze, A.Liesum

Key ref:

H.Matter et al. (2005). Structural requirements for factor Xa inhibition by 3-oxybenzamides with neutral P1 substituents: combining X-ray crystallography, 3D-QSAR, and tailored scoring functions. J Med Chem, 48, 3290-3312. PubMed id: 15857135 DOI: 10.1021/jm049187l

Date:

14-Mar-05 Release date: 08-Mar-06

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 53 a.a.

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 234 a.a.

Enzyme reactions

• Enzyme class: Chains A, B: E.C.3.4.21.6 - coagulation factor Xa.
• Reaction: Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.

DOI no: 10.1021/jm049187l

J Med Chem 48:3290-3312 (2005)

PubMed id: 15857135

Structural requirements for factor Xa inhibition by 3-oxybenzamides with neutral P1 substituents: combining X-ray crystallography, 3D-QSAR, and tailored scoring functions.

H.Matter, D.W.Will, M.Nazaré, H.Schreuder, V.Laux, V.Wehner.

ABSTRACT

The design, synthesis, and structure-activity relationship of 3-oxybenzamides as potent inhibitors of the coagulation protease factor Xa are described on the basis of X-ray structures, privileged structure motifs, and SAR information. A total of six X-ray structures of fXa/inhibitor complexes led us to identify the major protein-ligand interactions. The binding mode is characterized by a lipophilic dichlorophenyl substituent interacting with Tyr228 in the protease S1 pocket, while polar parts are accommodated in S4. This alignment in combination with docking allowed derivation of 3D-QSAR models and tailored scoring functions to rationalize biological affinity and provide guidelines for optimization. The resulting models showed good correlation coefficients and predictions of external test sets. Furthermore, they correspond to binding site topologies in terms of steric, electrostatic, and hydrophobic complementarity. Two approaches to derive tailored scoring functions combining binding site and ligand information led to predictive models with acceptable predictions of the external set. Good correlations to experimental affinities were obtained for both AFMoC (adaptation of fields for molecular comparison) and the novel TScore function. The SAR information from 3D-QSAR and tailored scoring functions agrees with all experimental data and provides guidelines and reasonable activity estimations for novel fXa inhibitors.