5QQP

FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl [(5E,8S)-8-[(4S)-4-(3-chlorophenyl)-2-oxopiperidin-1-yl]-2-oxo-1,3,4,7,8,10-hexahydro-2H-12,9-(azeno)-1,10-benzodiazacyclotetradecin-15-yl]carbamate

5QQP の概要

• エントリーDOI: 10.2210/pdb5qqp/pdb
• Group deposition: FXIa (G_1002075)
• 分子名称: Coagulation factor XI, methyl [(5E,8S)-8-[(4S)-4-(3-chlorophenyl)-2-oxopiperidin-1-yl]-2-oxo-1,3,4,7,8,10-hexahydro-2H-12,9-(azeno)-1,10-benzodiazacyclotetradecin-15-yl]carbamate, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: hydrolase, serine protease, blood coagulation factor, protein inhibitor complex
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28740.98

構造登録者

Sheriff, S. (登録日: 2019-05-20, 公開日: 2019-09-18, 最終更新日: 2021-05-12)

主引用文献

Clark, C.G.,Rossi, K.A.,Corte, J.R.,Fang, T.,Smallheer, J.M.,De Lucca, I.,Nirschl, D.S.,Orwat, M.J.,Pinto, D.J.P.,Hu, Z.,Wang, Y.,Yang, W.,Jeon, Y.,Ewing, W.R.,Myers Jr., J.E.,Sheriff, S.,Lou, Z.,Bozarth, J.M.,Wu, Y.,Rendina, A.,Harper, T.,Zheng, J.,Xin, B.,Xiang, Q.,Luettgen, J.M.,Seiffert, D.A.,Wexler, R.R.,Lam, P.Y.S.
Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability.
Bioorg.Med.Chem.Lett., 29:126604-126604, 2019

PubMed Abstract: This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.

PubMed: 31445854
DOI: 10.1016/j.bmcl.2019.08.008

実験手法

X-RAY DIFFRACTION (2.08 Å)