PDBsum entry 4zae

Hydrolase/hydrolase inhibitor

PDB id: 4zae

Contents

Protein chains

234 a.a.

55 a.a.

Ligands

4M1

NHE

Metals

_NA

Waters ×260

PDB id:

4zae

Name:

Hydrolase/hydrolase inhibitor

Title:

Development of a novel class of potent and selective fixa inhibitors

Structure:

Coagulation factor ix. Chain: a. Fragment: peptidase s1 domain (unp residues 227-461). Synonym: christmas factor,plasma thromboplastin component,ptc. Engineered: yes. Mutation: yes. Coagulation factor ix. Chain: b. Fragment: eg-like 2 domain (unp residues 131-191).

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f9. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Resolution:

1.86Å R-factor: 0.149 R-free: 0.174

Authors:

A.Hruza,P.Reichert

Key ref:

T.Zhang et al. (2015). Development of a novel class of potent and selective FIXa inhibitors. Bioorg Med Chem Lett, 25, 4945-4949. PubMed id: 25978966 DOI: 10.1016/j.bmcl.2015.04.057

Date:

13-Apr-15 Release date: 03-Jun-15

Protein chain

P00740  (FA9_HUMAN) -  Coagulation factor IX from Homo sapiens

Seq: 461 a.a.

Struc: 234 a.a.*

Protein chain

P00740  (FA9_HUMAN) -  Coagulation factor IX from Homo sapiens

Seq: 461 a.a.

Struc: 55 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.3.4.21.22 - coagulation factor IXa.
• Reaction: Hydrolyzes one Arg-|-Ile bond in factor X to form factor Xa.

DOI no: 10.1016/j.bmcl.2015.04.057

Bioorg Med Chem Lett 25:4945-4949 (2015)

PubMed id: 25978966

Development of a novel class of potent and selective FIXa inhibitors.

T.Zhang, P.Andre, T.J.Bateman, Y.H.Chen, K.Desai, K.Ellsworth, W.M.Geissler, L.Guo, A.Hruza, T.Jian, D.Meng, D.L.Parker, X.Qian, P.Reichert, E.C.Sherer, M.Shu, C.J.Smith, L.M.Sonatore, R.Tschirret-Guth, A.F.Nolting, R.Orr, L.C.Campeau, K.Araki, T.Nishimura, I.Sakurada, H.B.Wood.

ABSTRACT

Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.