Discovery of Novel 5‑Lipoxygenase-Activating Protein (FLAP) Inhibitors by Exploiting a Multistep Virtual Screening Protocol

Leukotrienes (LTs)
are proinflammatory mediators derived from arachidonic
acid (AA), which play significant roles in inflammatory diseases.
The 5-lipoxygenase-activating protein (FLAP) is an integral membrane
protein, which is essential for the initial step in LT biosynthesis.
The aim of this study was to discover novel and chemically diverse
FLAP inhibitors for treatment of inflammatory diseases requiring anti-LT
therapy. Both ligand- and structure-based approaches were applied
to explain the activities of known FLAP inhibitors in relation to
their predicted binding modes. We gained valuable insights into the
binding modes of the inhibitors by molecular modeling and generated
a multistep virtual screening (VS) workflow in which 6.2 million compounds
were virtually screened, and the molecular hypotheses were validated
by testing VS-hit compounds biologically. The most potent hit compounds
showed significant inhibition of FLAP-dependent cellular LT biosynthesis
with IC50 values in the range from 0.13 to 0.87 μM.
Collectively, this study provided novel bioactive chemotypes with
potential for further development as effective anti-inflammatory drugs.