title: Validation of flavonoids as potential dipeptidyl peptidase III inhibitors: Experimental and computational approach.
abstract: Fifteen flavonoids were studied for their inhibitory activity against human dipeptidyl peptidase III (hDPP III) combining an in vitro assay with an in silico molecular modeling study. All analyzed flavonoids showed inhibitory effects against hDPP III with the IC50values ranging from 22.0 to 437.2 μm. Our 3D QSAR studies indicate that the presence of hydrophilic regions at a flavonoid molecule increases its inhibitory activity, while the higher percentage of hydrophobic surfaces has negative impact on enzyme inhibition. Furthermore, molecular dynamics (MD) simulations of the complex of hDPP III with one of the most potent inhibitors, luteolin, were performed, and binding mode analysis revealed that the 3' and 4' hydroxyl group on B-ring as well as 5 and 7 hydroxyl group on A-ring helps luteolin to interact with the Asn391, Asn406, Tyr417, His450, Glu451, Val447, Glu512, Asn545, Gln566, and Arg572 residues. The MD results clearly provide valuable information explaining the importance of flavonoid hydroxyl groups in the mechanism for the binding pattern at the active site of hDPP III.
authors.affiliation: Faculty of Agriculture in Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia.
authors.forename: Dejan
authors.initials: D
authors.lastname: Agić
authors.affiliation: Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia.
authors.forename: Hrvoje
authors.identifier: 0000-0001-6692-6875
authors.initials: H
authors.lastname: Brkić
authors.affiliation: Ruđer Bošković Institute, Zagreb, Croatia.
authors.forename: Sanja
authors.initials: S
authors.lastname: Tomić
authors.affiliation: Ruđer Bošković Institute, Zagreb, Croatia.
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Karačić
authors.affiliation: Faculty of Agriculture in Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia.
authors.forename: Marija
authors.initials: M
authors.lastname: Špoljarević
authors.affiliation: Faculty of Agriculture in Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Lisjak
authors.affiliation: Faculty of Agriculture in Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia.
authors.forename: Drago
authors.initials: D
authors.lastname: Bešlo
authors.affiliation: Ruđer Bošković Institute, Zagreb, Croatia.
authors.forename: Marija
authors.initials: M
authors.lastname: Abramić
mesh_terms: D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011480:Protease Inhibitors / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D005419:Flavonoids; D011480:Protease Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100152:dipeptidyl peptidase III
keywords: dipeptidyl peptidase III; flavonoids; inhibitory activity; metallopeptidase; molecular dynamics