6TS5

Coagulation factor XI protease domain in complex with active site inhibitor

6TS5 の概要

• エントリーDOI: 10.2210/pdb6ts5/pdb
• 関連するPDBエントリー: 6T7P 6TS4
• 分子名称: Coagulation factor XI, 2-[2-[3-[(3~{S})-3-azanyl-2,3-dihydro-1-benzofuran-5-yl]-5-propan-2-yl-phenyl]ethoxy]-3-methoxy-benzoic acid, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: s1 protease, serine protease, structure-based drug design, active site directed inhibitor, hydrolase
• 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: 27748.47

構造登録者

Renatus, M.,Schiering, N. (登録日: 2019-12-20, 公開日: 2020-07-08, 最終更新日: 2024-11-13)

主引用文献

Lorthiois, E.,Roache, J.,Barnes-Seeman, D.,Altmann, E.,Hassiepen, U.,Turner, G.,Duvadie, R.,Hornak, V.,Karki, R.G.,Schiering, N.,Weihofen, W.A.,Perruccio, F.,Calhoun, A.,Fazal, T.,Dedic, D.,Durand, C.,Dussauge, S.,Fettis, K.,Tritsch, F.,Dentel, C.,Druet, A.,Liu, D.,Kirman, L.,Lachal, J.,Namoto, K.,Bevan, D.,Mo, R.,Monnet, G.,Muller, L.,Zessis, R.,Huang, X.,Lindsley, L.,Currie, T.,Chiu, Y.H.,Fridrich, C.,Delgado, P.,Wang, S.,Hollis-Symynkywicz, M.,Berghausen, J.,Williams, E.,Liu, H.,Liang, G.,Kim, H.,Hoffmann, P.,Hein, A.,Ramage, P.,D'Arcy, A.,Harlfinger, S.,Renatus, M.,Ruedisser, S.,Feldman, D.,Elliott, J.,Sedrani, R.,Maibaum, J.,Adams, C.M.
Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach.
J.Med.Chem., 63:8088-8113, 2020

PubMed Abstract: The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound , identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1' pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.

PubMed: 32551603
DOI: 10.1021/acs.jmedchem.0c00279

実験手法

X-RAY DIFFRACTION (1.29 Å)