Discovery of Novel 5-Lipoxygenase-Activating Protein (FLAP) Inhibitors by Exploiting a Multistep Virtual Screening Protocol. 2020

Abdurrahman Olgac, and Andrea Carotti, and Christian Kretzer, and Stephanie Zergiebel, and Andreas Seeling, and Ulrike Garscha, and Oliver Werz, and Antonio Macchiarulo, and Erden Banoglu
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06560 Yenimahalle, Ankara, Turkey.

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.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D000893 Anti-Inflammatory Agents Substances that reduce or suppress INFLAMMATION. Anti-Inflammatory Agent,Antiinflammatory Agent,Agents, Anti-Inflammatory,Agents, Antiinflammatory,Anti-Inflammatories,Antiinflammatories,Antiinflammatory Agents,Agent, Anti-Inflammatory,Agent, Antiinflammatory,Agents, Anti Inflammatory,Anti Inflammatories,Anti Inflammatory Agent,Anti Inflammatory Agents
D015289 Leukotrienes A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. Leukotriene
D016859 Lipoxygenase Inhibitors Compounds that bind to and inhibit that enzymatic activity of LIPOXYGENASES. Included under this category are inhibitors that are specific for lipoxygenase subtypes and act to reduce the production of LEUKOTRIENES. 5-Lipoxygenase Inhibitor,Lipoxygenase Inhibitor,12-Lipoxygenase Inhibitors,15-Lipoxygenase Inhibitors,5-Lipoxygenase Inhibitors,Arachidonate 12-Lipoxygenase Inhibitors,Arachidonate 15-Lipoxygenase Inhibitors,Arachidonate 5-Lipoxygenase Inhibitors,Inhibitors, Lipoxygenase,12 Lipoxygenase Inhibitors,12-Lipoxygenase Inhibitors, Arachidonate,15 Lipoxygenase Inhibitors,15-Lipoxygenase Inhibitors, Arachidonate,5 Lipoxygenase Inhibitor,5 Lipoxygenase Inhibitors,5-Lipoxygenase Inhibitors, Arachidonate,Arachidonate 12 Lipoxygenase Inhibitors,Arachidonate 15 Lipoxygenase Inhibitors,Arachidonate 5 Lipoxygenase Inhibitors,Inhibitor, 5-Lipoxygenase,Inhibitor, Lipoxygenase,Inhibitors, 12-Lipoxygenase,Inhibitors, 15-Lipoxygenase,Inhibitors, 5-Lipoxygenase,Inhibitors, Arachidonate 12-Lipoxygenase,Inhibitors, Arachidonate 15-Lipoxygenase,Inhibitors, Arachidonate 5-Lipoxygenase
D058927 5-Lipoxygenase-Activating Proteins Scaffolding proteins that play an important role in the localization and activation of 5-LIPOXYGENASE. 5-LO-Activating Protein,5-Lipoxygenase-Activating Protein,Arachidonate 5-Lipoxygenase Activating Protein,Arachidonate 5-Lipoxygenase Activating Proteins,5 LO Activating Protein,5 Lipoxygenase Activating Protein,5 Lipoxygenase Activating Proteins,Arachidonate 5 Lipoxygenase Activating Protein,Arachidonate 5 Lipoxygenase Activating Proteins

Related Publications

Abdurrahman Olgac, and Andrea Carotti, and Christian Kretzer, and Stephanie Zergiebel, and Andreas Seeling, and Ulrike Garscha, and Oliver Werz, and Antonio Macchiarulo, and Erden Banoglu
January 1993, Journal of lipid mediators,
Abdurrahman Olgac, and Andrea Carotti, and Christian Kretzer, and Stephanie Zergiebel, and Andreas Seeling, and Ulrike Garscha, and Oliver Werz, and Antonio Macchiarulo, and Erden Banoglu
June 2012, Bioorganic & medicinal chemistry,
Abdurrahman Olgac, and Andrea Carotti, and Christian Kretzer, and Stephanie Zergiebel, and Andreas Seeling, and Ulrike Garscha, and Oliver Werz, and Antonio Macchiarulo, and Erden Banoglu
August 2015, Bioorganic & medicinal chemistry,
Abdurrahman Olgac, and Andrea Carotti, and Christian Kretzer, and Stephanie Zergiebel, and Andreas Seeling, and Ulrike Garscha, and Oliver Werz, and Antonio Macchiarulo, and Erden Banoglu
October 1995, Journal of lipid mediators and cell signalling,
Abdurrahman Olgac, and Andrea Carotti, and Christian Kretzer, and Stephanie Zergiebel, and Andreas Seeling, and Ulrike Garscha, and Oliver Werz, and Antonio Macchiarulo, and Erden Banoglu
June 2021, Bioorganic & medicinal chemistry letters,
Abdurrahman Olgac, and Andrea Carotti, and Christian Kretzer, and Stephanie Zergiebel, and Andreas Seeling, and Ulrike Garscha, and Oliver Werz, and Antonio Macchiarulo, and Erden Banoglu
January 2015, PloS one,
Abdurrahman Olgac, and Andrea Carotti, and Christian Kretzer, and Stephanie Zergiebel, and Andreas Seeling, and Ulrike Garscha, and Oliver Werz, and Antonio Macchiarulo, and Erden Banoglu
January 2017, Future medicinal chemistry,
Abdurrahman Olgac, and Andrea Carotti, and Christian Kretzer, and Stephanie Zergiebel, and Andreas Seeling, and Ulrike Garscha, and Oliver Werz, and Antonio Macchiarulo, and Erden Banoglu
January 1997, Advances in experimental medicine and biology,
Abdurrahman Olgac, and Andrea Carotti, and Christian Kretzer, and Stephanie Zergiebel, and Andreas Seeling, and Ulrike Garscha, and Oliver Werz, and Antonio Macchiarulo, and Erden Banoglu
February 2008, Trends in pharmacological sciences,
Abdurrahman Olgac, and Andrea Carotti, and Christian Kretzer, and Stephanie Zergiebel, and Andreas Seeling, and Ulrike Garscha, and Oliver Werz, and Antonio Macchiarulo, and Erden Banoglu
August 1999, Bioorganic & medicinal chemistry letters,
Copied contents to your clipboard!