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

5I46 の概要

• エントリーDOI: 10.2210/pdb5i46/pdb
• 分子名称: 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)
• 機能のキーワード: glycoprotein, hydrolase, serine protease, plasma, blood coagulation factor, protein inhibitor complex, calcium-binding, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Secreted: P08709 P08709
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 35201.18

構造登録者

Wei, A. (登録日: 2016-02-11, 公開日: 2016-06-22, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.06 Å)