铅化合物
化学
结合位点
组合化学
极表面积
立体化学
虚拟筛选
对接(动物)
小分子
药物发现
分子
生物化学
体外
有机化学
医学
护理部
作者
Ola Fjellström,Sibel Akkaya,Hans-Georg Beisel,Per Eriksson,Karl M. Erixon,David Gustafsson,Ulrik Jurva,Daiwu Kang,David Karis,Wolfgang Knecht,V. Nerme,Ingrid Nilsson,Thomas Olsson,Alma Redzic,Robert Roth,Jenny Sandmark,Anna Tigerström,Linda Öster
出处
期刊:PLOS ONE
[Public Library of Science]
日期:2015-01-28
卷期号:10 (1): e0113705-e0113705
被引量:32
标识
DOI:10.1371/journal.pone.0113705
摘要
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.
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