title: Development of a potent 2-oxoamide inhibitor of secreted phospholipase A2 guided by molecular docking calculations and molecular dynamics simulations.
abstract: Inhibition of group IIA secreted phospholipase A2 (GIIA sPLA2) has been an important objective for medicinal chemists. We have previously shown that inhibitors incorporating the 2-oxoamide functionality may inhibit human and mouse GIIA sPLA2s. Herein, the development of new potent inhibitors by molecular docking calculations using the structure of the known inhibitor 7 as scaffold, are described. Synthesis and biological evaluation of the new compounds revealed that the long chain 2-oxoamide based on (S)-valine GK241 led to improved activity (IC50=143 nM and 68 nM against human and mouse GIIA sPLA2, respectively). In addition, molecular dynamics simulations were employed to shed light on GK241 potent and selective inhibitory activity.
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
authors.forename: Sofia
authors.initials: S
authors.lastname: Vasilakaki
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: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Avenue, Athens 11635, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Leonis
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Avenue, Athens 11635, Greece.
authors.forename: Manthos G
authors.initials: MG
authors.lastname: Papadopoulos
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.affiliation: Department of Chemistry and Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece. Electronic address: gkokotos@chem.uoa.gr.
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D054501:Group II Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D064801:Phospholipase A2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D064801:Phospholipase A2 Inhibitors; D011725:Pyridines; C034960:oxoamide; D054501:Group II Phospholipases A2
keywords: 2-Oxoamides; Docking; Inhibitors; Molecular dynamics; Secreted phospholipase A(2)