4CRC

Creating novel F1 inhibitors through fragment based lead generation and structure aided drug design

4CRC の概要

• エントリーDOI: 10.2210/pdb4crc/pdb
• 関連するPDBエントリー: 4CR5 4CR9 4CRA 4CRB 4CRD 4CRE 4CRF 4CRG
• 分子名称: COAGULATION FACTOR XI, (2S)-2-[[(E)-3-[5-chloranyl-2-(1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enoyl]amino]-3-phenyl-N-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]propanamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: hydrolase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Secreted: P03951
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27403.42

構造登録者

Sandmark, J.,Oster, L.,Fjellstrom, O.,Akkaya, S.,Beisel, H.G.,Eriksson, P.O.,Erixon, K.,Gustafsson, D.,Jurva, U.,Kang, D.,Karis, D.,Knecht, W.,Nerme, V.,Nilsson, I.,Olsson, T.,Redzic, A.,Roth, R.,Tigerstrom, A. (登録日: 2014-02-26, 公開日: 2015-02-11, 最終更新日: 2024-10-23)

主引用文献

Fjellstrom, O.,Akkaya, S.,Beisel, H.,Eriksson, P.,Erixon, K.,Gustafsson, D.,Jurva, U.,Kang, D.,Karis, D.,Knecht, W.,Nerme, V.,Nilsson, I.,Olsson, T.,Redzic, A.,Roth, R.,Sandmark, J.,Tigerstrom, A.,Oster, L.
Creating Novel Activated Factor Xi Inhibitors Through Fragment Based Lead Generation and Structure Aided Drug Design.
Plos One, 10:13705-, 2015

PubMed Abstract: Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1'-S2' FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1'-S2' binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC50 of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1'-S2' binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds.

PubMed: 25629509
DOI: 10.1371/JOURNAL.PONE.0113705

実験手法

X-RAY DIFFRACTION (1.6 Å)