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

Abstract

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.

Combined Machine Learning and GRID-Independent Molecular Descriptor (GRIND) Models to Probe the Activity Profiles of 5-Lipoxygenase Activating Protein Inhibitors

“…Overall, our GRIND model suggested that (1) two hydrophobic features should be present at a mutual distance of 16.00–16.40 Å, (2) one hydrophobic and hydrogen bond acceptor feature should be present at a distance of 16.40–16.80 Å, (3) the distance between hydrophobic and steric feature should be 18.00–18.40 Å, and (4) and it should be 17.20–17.60 Å between hydrogen bond acceptor and steric features. The importance of hydrophobic and hydrogen bond acceptor features has also been demonstrated by previous studies ( Temml et al, 2017 ; Olgac et al, 2020 ).…”

“…This further strengthened our docking outcomes as all of these amino acid residues are involved in making extensive π-H interactions with dataset compounds. Additionally, a recent pharmacophore study of Olgac et al revealed that four hydrophobic features are important in most potent indole- and oxadiazole-based FLAP inhibitors ( Olgac et al, 2020 ).…”

“…Mostly FLAP modulators were synthesized and pharmacologically tested and optimized through SAR (structure–activity relationship) studies. Some candidates were also identified by virtual screening from a ligand-based pharmacophore built upon smaller datasets ( Banoglu et al, 2012 ; Temml et al, 2017 ; Olgac et al, 2020 ). Here, in this study, advanced machine learning (ML) techniques along with classical modeling strategies are adapted to shed light on important 2D and 3D anti-inflammatory properties of a diverse set of inhibitors targeting FLAP.…”

MicroRNA-146a promotes proliferation, migration, and invasion of HepG2 via regulating FLAP

“…Currently, drugs targeting the FLAP protein, such as BAY-X1005 and AM-103/GSK2190914, have been actively developed in humans to reduce the incidence of ischemic myocardial infarction and to treat asthma [ 45 , 46 ]. Although many studies have shown that inhibition of FLAP can significantly improve ischemic myocardial infarction [ 45 ], asthma [ 46 ], arthritis [ 47 ], breast cancer [ 23 ], lung cancer [ 25 ], and other diseases, the results of this study showed that FLAP can promote apoptosis of HepG2 cells and inhibit migration and proliferation of HepG2 cells. This may be due to differences in characteristics of different tumor cells.…”

MicroRNA-146a promotes proliferation, migration, and invasion of HepG2 via regulating FLAP

“…Currently, drugs targeting the FLAP protein, such as BAY-X1005 and AM-103/GSK2190914, have been actively developed in humans to reduce the incidence of ischemic myocardial infarction and to treat asthma [19,20]. Although many studies have shown that inhibition of FLAP can signi cantly improve ischemic myocardial infarction [19], asthma [20], arthritis [41], breast cancer[18], lung cancer [22], and other diseases, the results of this study showed that FLAP can promote apoptosis of HepG2 cells and inhibit migration and proliferation of HepG2 cells. This may be due to differences in characteristics of different tumor cells.…”