Virtual screening and in vitro assays of novel hits as promising DPP-4 inhibitors.

Autor: Pantaleão SQ; Center for Sciences Natural and Human, Federal University of ABC, 09210-170, Santo André, SP, Brazil., Philot EA; Center for Mathematics, Computing and Cognition, Federal University of ABC, 09210-170, Santo André, SP, Brazil., de Paula H; Center for Exact, Natural and Health Sciences, Federal University of Espírito Santo, 29075-910, Vitória, ES, Brazil., Inês de Sairre M; Center for Sciences Natural and Human, Federal University of ABC, 09210-170, Santo André, SP, Brazil., Lima AN; Department of Medical Genetics and Genomic Medicine, Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), University of Campinas, Campinas, SP, Brazil., Pires LM; Laboratory of Genetics and Molecular Biology, University of Franca, 14404-600, Franca, SP, Brazil., Alves Dos Santos R; Laboratory of Genetics and Molecular Biology, University of Franca, 14404-600, Franca, SP, Brazil., Scott AL; Center for Mathematics, Computing and Cognition, Federal University of ABC, 09210-170, Santo André, SP, Brazil., Honorio KM; Center for Sciences Natural and Human, Federal University of ABC, 09210-170, Santo André, SP, Brazil; School of Arts, Sciences and Humanities, University of São Paulo, 03828-0000, São Paulo, SP, Brazil. Electronic address: kmhonorio@usp.br.
Jazyk: angličtina
Zdroj: Biochimie [Biochimie] 2022 Mar; Vol. 194, pp. 43-50. Date of Electronic Publication: 2021 Dec 21.
DOI: 10.1016/j.biochi.2021.12.007
Abstrakt: Diabetes is a metabolic disorder that presents hyperglycemia and vascular complications due to the non-production of insulin or its inappropriate use by the body. One of the strategies to treat diabetes is the inhibition of dipeptidyl peptidase-4 (DPP-4) and it is interesting to conduct virtual screening studies to search for new inhibitors of the DPP-4 enzyme. This study involves a virtual screening using the crystallographic structure of DPP-4 and a compound subset from the ZINC database. To filter this compound subset, we used some physicochemical properties, positioning at the three DPP-4 binding sites, molecular interactions, and ADME-Tox properties. The conformations of ligands obtained from AutoDock Vina were analyzed using a consensus with other algorithms (AutoDock and GOLD). The compounds selected from virtual screening were submitted to biological assays using the "DPPIV-Glo™ protease assay". Cytotoxicity tests were also performed. One promising compound (ZINC1572309) established interactions with important residues at the binding site. The results of the ADME-Tox prediction for ZINC1572309 were compared with a reference drug (sitagliptin). The cytotoxicity of sitagliptin and ZINC1572309 were evaluated using the XTT short-term cytotoxic assay, including normal and tumor cell lines to observe the cellular response to inhibitor treatment at different genetic bases. Both compounds (ZINC1572309 and the reference drug - sitagliptin) also inhibited DPP-4 activity, suggesting interesting biological effects of the selected compound at non-cytotoxic concentrations. Therefore, from in silico and in vitro studies, a potential hit as DPP-4 inhibitor was discovered and it can be structurally optimized to achieve suitable activity and pharmacokinetic profiles.
(Copyright © 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)
Databáze: MEDLINE
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