PDBsum entry 3sw2

Hydrolase/hydrolase inhibitor

PDB id: 3sw2

Contents

Protein chains

56 a.a.

233 a.a.

Ligands

FI1

GOL

Metals

_NA

_CA

Waters ×83

PDB id:

3sw2

Name:

Hydrolase/hydrolase inhibitor

Title:

X-ray crystal structure of human fxa in complex with 6-chloro-n-((3s)- 2-oxo-1-(2-oxo-2-((5s)-8-oxo-5,6-dihydro-1h-1,5-methanopyrido[1,2- a][1,5]diazocin-3(2h,4h,8h)-yl)ethyl)piperidin-3-yl)naphthalene-2- sulfonamide

Structure:

Coagulation factor x. Chain: a. Fragment: factor x light chain (unp residues 85-178). Synonym: stuart factor, stuart-prower factor. Coagulation factor x. Chain: b. Fragment: activated factor xa heavy chain (unp residues 235-472). Synonym: stuart factor, stuart-prower factor. Ec: 3.4.21.6

Source:

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

Resolution:

2.42Å R-factor: 0.199 R-free: 0.262

Authors:

H.E.Klei

Key ref:

Y.Shi et al. (2011). Arylsulfonamidopiperidone derivatives as a novel class of factor Xa inhibitors. Bioorg Med Chem Lett, 21, 7516-7521. PubMed id: 22041058

Date:

13-Jul-11 Release date: 16-Nov-11

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 56 a.a.

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 233 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.

Bioorg Med Chem Lett 21:7516-7521 (2011)

PubMed id: 22041058

Arylsulfonamidopiperidone derivatives as a novel class of factor Xa inhibitors.

Y.Shi, S.P.O'Connor, D.Sitkoff, J.Zhang, M.Shi, S.N.Bisaha, Y.Wang, C.Li, Z.Ruan, R.M.Lawrence, H.E.Klei, K.Kish, E.C.Liu, S.M.Seiler, L.Schweizer, T.E.Steinbacher, W.A.Schumacher, J.A.Robl, J.E.Macor, K.S.Atwal, P.D.Stein.

ABSTRACT

The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide-valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC(50) of 7 nM and EC(2×PT) of 1.7 μM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide-valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets.