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Chem Biol Drug Des. 2017 Apr;89(4):619-627. doi: 10.1111/cbdd.12887. Epub 2016 Nov 19.

Validation of flavonoids as potential dipeptidyl peptidase III inhibitors: Experimental and computational approach.

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Faculty of Agriculture in Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia.
Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia.
Ruđer Bošković Institute, Zagreb, Croatia.


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 IC50 values 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.


dipeptidyl peptidase III; flavonoids; inhibitory activity; metallopeptidase; molecular dynamics

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