title: Inhibition of Peroxidase Activity of Cytochrome c: De Novo Compound Discovery and Validation.
abstract: Cytochrome c (cyt c) release from mitochondria is accepted to be the point of no return for eliciting a cascade of interactions that lead to apoptosis. A strategy for containing sustained apoptosis is to reduce the mitochondrial permeability pore opening. Pore opening is enhanced by peroxidase activity of cyt c gained upon its complexation with cardiolipin in the presence of reactive oxygen species. Blocking access to the heme group has been proposed as an effective intervention method for reducing, if not eliminating, the peroxidase activity of cyt c. In the present study, using a combination of druggability simulations, pharmacophore modeling, virtual screening, and in vitro fluorescence measurements to probe peroxidase activity, we identified three repurposable drugs and seven compounds that are validated to effectively inhibit the peroxidase activity of cyt c.
authors.affiliation: Department of Computational and Systems Biology, School of Medicine (A.B., F.H., I.B.), and Department of Environmental and Occupational Health (A.A.K., H.B., V.E.K.), University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Bakan
authors.affiliation: Department of Computational and Systems Biology, School of Medicine (A.B., F.H., I.B.), and Department of Environmental and Occupational Health (A.A.K., H.B., V.E.K.), University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Alexandr A
authors.initials: AA
authors.lastname: Kapralov
authors.affiliation: Department of Computational and Systems Biology, School of Medicine (A.B., F.H., I.B.), and Department of Environmental and Occupational Health (A.A.K., H.B., V.E.K.), University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Hulya
authors.initials: H
authors.lastname: Bayir
authors.affiliation: Department of Computational and Systems Biology, School of Medicine (A.B., F.H., I.B.), and Department of Environmental and Occupational Health (A.A.K., H.B., V.E.K.), University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Feizhou
authors.initials: F
authors.lastname: Hu
authors.affiliation: Department of Computational and Systems Biology, School of Medicine (A.B., F.H., I.B.), and Department of Environmental and Occupational Health (A.A.K., H.B., V.E.K.), University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.affiliation: Department of Computational and Systems Biology, School of Medicine (A.B., F.H., I.B.), and Department of Environmental and Occupational Health (A.A.K., H.B., V.E.K.), University of Pittsburgh, Pittsburgh, Pennsylvania bahar@pitt.edu.
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010544:Peroxidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D010544:Peroxidases; D003576:Electron Transport Complex IV