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 IC 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.

Triarylborane Dyes as a Novel Non-Covalent and Non-Inhibitive Fluorimetric Markers for DPP III Enzyme

“…For that purpose, we have chosen one type of peptidase enzyme, human DPP III (hDPP III), for which we previously reported several types of fluorescent markers [ 13 , 14 ], which also showed promising inhibitory activity of the enzyme action. As hDPP III could eventually cleave the peptide bond in 2 , we first performed fluorimetric titrations with mutant hDPP III-E451A, which due to its mutation at the active site, cannot cleave peptide bonds [ 11 ]. The emission increase obtained for 1 ( Figure 5 ) and 2 ( Supplementary Information, Figure S9 ), and binding constants ( 1 : logKs = 6.6; 2 : logKs = 6.4) were very similar to those obtained for BSA, suggesting similar types of binding interactions.…”

“…DPP III is broadly distributed in mammalian tissues and thought to contribute to the final steps of normal intracellular protein catabolism, although its exact role(s) are still unclear. DPP III shows pronounced affinity for some bioactive peptides (angiotensins II, III, IV, and opioid peptides), and also flavonoids [ 11 , 12 ], as well as for many different peptidomimetics, many of which contain large aromatic moieties (naphthalene, phenanthridine, cyanine, pyrene, etc.) [ 13 , 14 ].…”

Aprotinin interacts with substrate-binding site of human dipeptidyl peptidase III

“…DPP III catalyzes the hydrolysis of penultimate peptide bond, liberating the dipeptides sequentially from the N-termini of its substrates. Human DPP III is the best characterized member of the family, in terms of biochemistry, structural biology and computational dynamics (Abrami c et al, 1988(Abrami c et al, , 2004bAgi c et al, 2017;Bar sun, Jaj canin, Vukeli c, Spoljari c, & Abrami c, 2007;Bezerra et al, 2012;Chen & Barrett, 2004; Kara ci c, Spoljari c, Ro zman, & Abrami c, 2012; Kumar et al, 2016;Shimamori, Watanabe, & Fujimoto, 1986;Tomi c, Gonzalez, & Tomi c, 2012;Tomi c & Tomi c, 2014;Tomi c, Kova cevi c, & Tomi c, 2016). It is a monomeric acidic protein (pI$4.6) with 737 amino acids in the polypeptide chain and molecular mass of 82 500 Da (Abrami c et al, 1988(Abrami c et al, , 2000Chen & Barrett, 2004).…”

Dipeptidyl peptidase 3, a novel protease from Leishmania braziliensis

“…donovani , one of the species that causes visceral leishmaniasis [ 26 ]. Due to the crucial functions of DPP3 in other organisms, the availability of specific inhibitors [ 21 , 22 , 31 , 32 ], and its confirmed presence in other relevant Leishmania species ( L . donovani ); the aim of this work was to characterize the L .…”