title: Genome wide analysis and comparative docking studies of new diaryl furan derivatives against human cyclooxygenase-2, lipoxygenase, thromboxane synthase and prostacyclin synthase enzymes involved in inflammatory pathway.
abstract: In an effort to develop potent anti-inflammatory and antithrombotic drugs, a series of new 4-(2-phenyltetrahydrofuran-3-yl) benzene sulfonamide analogs were designed and docked against homology models of human cyclooxygenase-2 (COX-2), lipoxygenase and thromboxane synthase enzymes built using MODELLER 7v7 software and refined by molecular dynamics for 2 ns in a solvated layer. Validation of these homology models by procheck, verify-3D and ERRAT programs revealed that these models are highly reliable. Docking studies of 4-(2-phenyltetrahydrofuran-3-yl) benzene sulfonamide analogs designed by substituting different chemical groups on benzene rings replacing 1H pyrazole in celecoxib with five membered thiophene, furan, 1H pyrrole, 1H imidazole, thiazole and 1,3-oxazole showed that diaryl furan molecules showed good binding affinity towards mouse COX-2. Further, docking studies of diaryl furan derivatives are likely to have superior thromboxane synthase and COX-2 selectivity. Docking studies against site directed mutagenesis of Arg120Ala, Ser530Ala, Ser530Met and Tyr355Phe enzymes displayed the effect of inhibition of COX-2. Drug likeliness and activity decay for these inhibitors showed that these molecules act as best drugs at very low concentrations.
authors.affiliation: Department of Genetics, Osmania University, Hyderabad 500 007, India.
authors.forename: P Nataraj
authors.initials: PN
authors.lastname: Sekhar
authors.forename: L Ananda
authors.initials: LA
authors.lastname: Reddy
authors.forename: Marc
authors.initials: M
authors.lastname: De Maeyer
authors.forename: K Praveen
authors.initials: KP
authors.lastname: Kumar
authors.forename: Y S
authors.initials: YS
authors.lastname: Srinivasulu
authors.forename: M S L
authors.initials: MS
authors.lastname: Sunitha
authors.forename: I S N
authors.initials: IS
authors.lastname: Sphoorthi
authors.forename: G
authors.initials: G
authors.lastname: Jayasree
authors.forename: A Maruthi
authors.initials: AM
authors.lastname: Rao
authors.forename: V S
authors.initials: VS
authors.lastname: Kothekar
authors.forename: P V B S
authors.initials: PV
authors.lastname: Narayana
authors.forename: P B Kavi
authors.initials: PB
authors.lastname: Kishor
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D051545:Cyclooxygenase 1 / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000737:chemistry*; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000201:enzymology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008084:Lipoxygenase / Q000737:chemistry*; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010802:Phylogeny; D017433:Protein Structure, Secondary; D015203:Reproducibility of Results; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D005663:Furans; D016859:Lipoxygenase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D008084:Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase; C039281:furan