PDBsum entry 5i46

Hydrolase/hydrolase inhibitor

PDB id: 5i46

Contents

Protein chains

254 a.a.

55 a.a.

Ligands

67O

SO4 ×3

MES

Metals

_CA

Waters ×209

References listed in PDB file

Key reference

• Title: Atropisomer control in macrocyclic factor viia inhibitors.
• Authors: P.W.Glunz, L.Mueller, D.L.Cheney, V.Ladziata, Y.Zou, N.R.Wurtz, A.Wei, P.C.Wong, R.R.Wexler, E.S.Priestley.
• Ref.: J Med Chem, 2016, 59, 4007-4018. [DOI no: 10.1021/acs.jmedchem.6b00244]
• PubMed id: 27015008

Abstract

Incorporation of a methyl group onto a macrocyclic FVIIa inhibitor improves potency 10-fold but is accompanied by atropisomerism due to restricted bond rotation in the macrocyclic structure, as demonstrated by NMR studies. We designed a conformational constraint favoring the desired atropisomer in which this methyl group interacts with the S2 pocket of FVIIa. A macrocyclic inhibitor incorporating this constraint was prepared and demonstrated by NMR to reside predominantly in the desired conformation. This modification improved potency 180-fold relative to the unsubstituted, racemic macrocycle and improved selectivity. An X-ray crystal structure of a closely related analogue in the FVIIa active site was obtained and matches the NMR and modeled conformations, confirming that this conformational constraint does indeed direct the methyl group into the S2 pocket as designed. The resulting rationally designed, conformationally stable template enables further optimization of these macrocyclic inhibitors.