Creating novel activated factor XI inhibitors through fragment based lead generation and structure aided drug design

PLoS One. 2015 Jan 28;10(1):e0113705. doi: 10.1371/journal.pone.0113705. eCollection 2015.

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.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design*
  • Drug Evaluation, Preclinical* / methods
  • Factor XIa / antagonists & inhibitors
  • Factor XIa / chemistry*
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptide Library
  • Protein Binding
  • Quantitative Structure-Activity Relationship*
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / pharmacology

Substances

  • Ligands
  • Peptide Library
  • Serine Proteinase Inhibitors
  • Factor XIa

Grant support

The authors have no support or funding to report.