PDBsum entry 4zxy

Hydrolase/hydrolase inhibitor

PDB id: 4zxy

Contents

Protein chains

250 a.a.

55 a.a.

Ligands

4T1

SO4 ×3

GOL

Metals

_CA

Waters ×196

References listed in PDB file

Key reference

• Title: Structure-Based design of macrocyclic coagulation factor viia inhibitors.
• Authors: E.S.Priestley, D.L.Cheney, I.Delucca, A.Wei, J.M.Luettgen, A.R.Rendina, P.C.Wong, R.R.Wexler.
• Ref.: J Med Chem, 2015, 58, 6225-6236. [DOI no: 10.1021/acs.jmedchem.5b00788]
• PubMed id: 26151189

Abstract

On the basis of a crystal structure of a phenylpyrrolidine lead and subsequent molecular modeling results, we designed and synthesized a novel series of macrocyclic FVIIa inhibitors. The optimal 16-membered macrocycle was 60-fold more potent than an acyclic analog. Further potency optimization by incorporation of P1' alkyl sulfone and P2 methyl groups provided a macrocycle with TF/FVIIa Ki = 1.6 nM, excellent selectivity against a panel of seven serine proteases, and FVII-deficient prothrombin time EC2x = 1.2 μM. Discovery of this potent, selective macrocyclic scaffold opens new possibilities for the development of orally bioavailable FVIIa inhibitors.