Creating novel activated factor XI inhibitors through fragment based lead generation and structure aided drug design
| Autor: | David Gustafsson, Ingemar Nilsson, Ola Fjellström, Per-Olof Eriksson, Karl Erixon, Wolfgang Knecht, Hans-Georg Beisel, Alma Redzic, Robert G. Roth, Jenny Sandmark, Daiwu Kang, Viveca Nerme, Linda Öster, David Karis, Ulrik Jurva, Tommy Olsson, Sibel Akkaya, Anna Tigerström |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Serine Proteinase Inhibitors Molecular Sequence Data Drug Evaluation Preclinical Molecular Conformation Quantitative Structure-Activity Relationship lcsh:Medicine Plasma protein binding Crystallography X-Ray Ligands Factor XIa Polar surface area Peptide Library Hydrolase Humans Amino Acid Sequence Binding site lcsh:Science Peptide library Nuclear Magnetic Resonance Biomolecular Binding Sites Multidisciplinary Chemistry lcsh:R Combinatorial chemistry Structural biology Biochemistry Docking (molecular) Drug Design lcsh:Q Research Article Protein Binding |
| Zdroj: | 'PloS One ', vol: 10, pages: e0113705-1-e0113705-42 (2015) PLoS ONE, Vol 10, Iss 1, p e0113705 (2015) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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