title: Development of Potent and Selective Inhibitors for Group VIA Calcium-Independent Phospholipase A2 Guided by Molecular Dynamics and Structure-Activity Relationships.
abstract: The development of inhibitors for phospholipase A2 (PLA2) is important in elucidating the enzymes implication in various biological pathways. PLA2 enzymes are an important pharmacological target implicated in various inflammatory diseases. Computational chemistry, organic synthesis, and in vitro assays were employed to develop potent and selective inhibitors for group VIA calcium-independent PLA2. A set of fluoroketone inhibitors was studied for their binding mode with two human cytosolic PLA2 enzymes: group IVA cPLA2 and group VIA iPLA2. New compounds were synthesized and assayed toward three major PLA2s. This study led to the development of four potent and selective thioether fluoroketone inhibitors as well as a thioether keto-1,2,4-oxadiazole inhibitor for GVIA iPLA2, which will serve as lead compounds for future development and studies. The keto-1,2,4-oxadiazole functionality with a thioether is a novel structure, and it will be used as a lead to develop inhibitors with higher potency and selectivity toward GVIA iPLA2.
authors.affiliation: Department of Pharmacology and Department of Chemistry and Biochemistry, School of Medicine, University of California, San Diego , La Jolla, California 92093-0601, United States.
authors.forename: Varnavas D
authors.initials: VD
authors.lastname: Mouchlis
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens , Panepistimiopolis, Athens 15771, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Limnios
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens , Panepistimiopolis, Athens 15771, Greece.
authors.forename: Maroula G
authors.initials: MG
authors.lastname: Kokotou
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens , Panepistimiopolis, Athens 15771, Greece.
authors.forename: Efrosini
authors.initials: E
authors.lastname: Barbayianni
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens , Panepistimiopolis, Athens 15771, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
authors.affiliation: Department of Pharmacology and Department of Chemistry and Biochemistry, School of Medicine, University of California, San Diego , La Jolla, California 92093-0601, United States.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.affiliation: Department of Pharmacology and Department of Chemistry and Biochemistry, School of Medicine, University of California, San Diego , La Jolla, California 92093-0601, United States.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
mesh_terms: D002118:Calcium / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D064801:Phospholipase A2 Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D054467:Phospholipases A2 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry
chemical_list: D064801:Phospholipase A2 Inhibitors; D013440:Sulfides; D054467:Phospholipases A2; D002118:Calcium