Experimental and computational evaluation of dipeptidyl peptidase III inhibitors based on quinazolinone-Schiff’s bases

Agić, Dejan; Karnaš, Maja; Tomić, Sanja; Komar, Mario; Karačić, Zrinka; Rastija, Vesna; Bešlo, Drago; Šubarić, Domagoj; Molnar, Maja (2023) Experimental and computational evaluation of dipeptidyl peptidase III inhibitors based on quinazolinone-Schiff’s bases. Journal of Biomolecular Structure and Dynamics, 41 (16). pp. 7567-7581. ISSN 0739-1102

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Abstract

Dipeptidyl peptidase III (DPP III) is a zinc-dependent enzyme that sequentially hydrolyzes biologically active peptides by cleaving dipeptides from their N-termini. Although its fundamental role is not been fully elucidated, human DPP III (hDPP III) has been recognized in several pathophysiological processes of interest for drug development. In this article 27 quinazolinone-Schiff’s bases were studied for their inhibitory activity against hDPP III combining an in vitro experiment with a computational approach. The biochemical assay showed that most compounds exhibited inhibitory activity at the 100 μM concentration. The best QSAR model included descriptors from the following 2D descriptor groups: information content indices, 2D autocorrelations, and edge adjacency indices. Five compounds were found to be the most potent inhibitors with IC50 values below 10 µM, while molecular docking predicted that these compounds bind to the central enzyme cleft and interact with residues of the substrate binding subsites. Molecular dynamics simulations of the most potent inhibitor (IC50=0.96 µM) provided valuable information explaining the role of PHE109, ARG319, GLU327, GLU329, and ILE386 in the mechanism of the inhibitor binding and stabilization. This is the first study that gives insight into quinazolinone-Schiff’s bases binding to this metalloenzyme.

Item Type:	Article
Uncontrolled Keywords:	Dipeptidyl peptidase III; inhibitor; molecular modeling; quinazolinone-Schiff’s bases
Subjects:	NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions:	Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type Biološka važnost dipeptidil peptidaze III i njezin utjecaj na zdravlje čovjeka-DPP3BioRe Sanja Tomić; Hrvoje Brkić IP-2018-01-2936 HRZZ Zelene tehnologije u sintezi heterocikličkih spojeva-GREENNESS Maja Molnar UIP-2017-05-6593 HRZZ
Depositing User:	Zrinka Karačić
Date Deposited:	07 Jan 2026 15:39
URI:	http://fulir.irb.hr/id/eprint/10746
DOI:	10.1080/07391102.2022.2123044

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