title: Inhibition of secreted phospholipases A₂ by 2-oxoamides based on α-amino acids: Synthesis, in vitro evaluation and molecular docking calculations.
abstract: Group IIA secreted phospholipase A₂ (GIIA sPLA₂) is a member of the mammalian sPLA₂ enzyme family and is associated with various inflammatory conditions. In this study, the synthesis of 2-oxoamides based on α-amino acids and the in vitro evaluation against three secreted sPLA₂s (GIIA, GV and GX) are described. The long chain 2-oxoamide GK126 based on the amino acid (S)-leucine displayed inhibition of human and mouse GIIA sPLA₂s (IC₅₀ 300nM and 180nM, respectively). It also inhibited human GV sPLA₂ with similar potency, while it did not inhibit human GX sPLA₂. The elucidation of the stereoelectronic characteristics that affect the in vitro activity of these compounds was achieved by using a combination of simulated annealing to sample low-energy conformations before the docking procedure, and molecular docking calculations.
authors.affiliation: Department of Chemistry, University of Athens, Greece.
authors.forename: Varnavas D
authors.initials: VD
authors.lastname: Mouchlis
authors.forename: Victoria
authors.initials: V
authors.lastname: Magrioti
authors.forename: Efrosini
authors.initials: E
authors.lastname: Barbayianni
authors.forename: Nathan
authors.initials: N
authors.lastname: Cermak
authors.forename: Rob C
authors.initials: RC
authors.lastname: Oslund
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Mavromoustakos
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D004791:Enzyme Inhibitors; D011725:Pyridines; C034960:oxoamide; D054497:Phospholipases A2, Secretory