5I46

Factor VIIA in complex with the inhibitor (2R,15R)-2-[(1-aminoisoquinolin-6-yl)amino]-8-fluoro-7-hydroxy-4,15,17-trimethyl-13-oxa-4,11-diazatricyclo[14.2.2.1~6,10~]henicosa-1(18),6(21),7,9,16,19-hexaene-3,12-dione

Summary for 5I46

• Entry DOI: 10.2210/pdb5i46/pdb
• Descriptor: Coagulation factor VII (Heavy Chain), Coagulation factor VII (Light Chain), (2R,15R)-2-[(1-aminoisoquinolin-6-yl)amino]-8-fluoro-7-hydroxy-4,15,17-trimethyl-13-oxa-4,11-diazatricyclo[14.2.2.1~6,10~]henicosa-1(18),6(21),7,9,16,19-hexaene-3,12-dione, ... (7 entities in total)
• Functional Keywords: glycoprotein, hydrolase, serine protease, plasma, blood coagulation factor, protein inhibitor complex, calcium-binding, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: P08709 P08709
• Total number of polymer chains: 2
• Total formula weight: 35201.18

Authors

Wei, A. (deposition date: 2016-02-11, release date: 2016-06-22, Last modification date: 2024-11-20)

Primary citation

Glunz, P.W.,Mueller, L.,Cheney, D.L.,Ladziata, V.,Zou, Y.,Wurtz, N.R.,Wei, A.,Wong, P.C.,Wexler, R.R.,Priestley, E.S.
Atropisomer Control in Macrocyclic Factor VIIa Inhibitors.
J.Med.Chem., 59:4007-4018, 2016

PubMed 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.

PubMed: 27015008
DOI: 10.1021/acs.jmedchem.6b00244

Experimental method

X-RAY DIFFRACTION (2.06 Å)