title: Virtual screening and biological evaluation of novel antipyretic compounds.
abstract: Due to the absence of safety of the antipyretics to patients with cardiovascular dysfunction, new targets to treat inflammation have been pursued. mPGES-1 is a promising target because its inhibition would not cause the side-effects related to COX inhibition. To identify novel inhibitors of mPGES-1, we developed a ligand-based pharmacophore model that differentiates true inhibitors from decoys and enlightens the structure-activity relationships for known mPGES-1 inhibitors. The model (four hydrophobic centers, two hydrogen bond acceptor and two hydrogen bond donor points) was employed to select lead-like compounds from ZINC database for in vivo evaluation. Among the 18 compounds selected, five inhibited the fever induced by LPS. The most potent compound (5-(4-fluorophenyl)-3-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-2,3dihydro-1,3,4-oxadiazol-2-one) is active peripherally (i.v.) or centrally (i.c.v.) (82.18% and 112% reduction, respectively) and reduces (69.13%) hypothalamic PGE2production, without significant COX-1/2 inhibition. In conclusion, our in silico approach leads to the selection of a compound that presents the chemical features to inhibit mPGES-1 and reduces fever induced by LPS. Furthermore, the in vivo and in vitro results support the hypothesis that its mechanism of action does not depend on COX inhibition. Hence, it can be considered a promising lead compound for antipyretic development, once it would not have the side-effects of COX-1/2 inhibitors.
authors.affiliation: Laboratory of Pharmacology of Inflammation and Fever, Faculty of Pharmacy, Federal University of Bahia, Salvador, BA, Brazil.|Laboratory of Bioinformatics and Molecular Modeling, Faculty of Pharmacy, Federal University of Bahia, Salvador, BA, Brazil.
authors.forename: Thamires Quadros
authors.initials: TQ
authors.lastname: Froes
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Miriam C C
authors.initials: MCC
authors.lastname: Melo
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Gloria E P
authors.initials: GEP
authors.lastname: Souza
authors.affiliation: Laboratory of Bioinformatics and Molecular Modeling, Faculty of Pharmacy, Federal University of Bahia, Salvador, BA, Brazil.
authors.forename: Marcelo Santos
authors.initials: MS
authors.lastname: Castilho
authors.affiliation: Laboratory of Pharmacology of Inflammation and Fever, Faculty of Pharmacy, Federal University of Bahia, Salvador, BA, Brazil.
authors.forename: Denis M
authors.identifier: http://orcid.org/0000-0003-1532-7332
authors.initials: DM
authors.lastname: Soares
mesh_terms: D000818:Animals; D058633:Antipyretics / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D055808:Drug Discovery; D005334:Fever / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008297:Male; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D017208:Rats, Wistar
chemical_list: C586624:1,3,4-oxadiazol-2(3H)-one; D058633:Antipyretics; D008024:Ligands; D010069:Oxadiazoles; D000071876:Prostaglandin-E Synthases; C497818:Ptges protein, rat; D015232:Dinoprostone
keywords: LPS; PGE2; fever; mPGES-1; virtual screening