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

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. Drug design and discovery of hits as effective and safe DPP-4 inhibitors to help the treatment of type II diabetes mellitus. [Display omitted] • Identification of a hit as inhibitor of dipeptidyl peptidase-4 (DPP-4) from in silico and in vitro studies. • Some in silico techniques were employed to assess the compound database, such as molecular docking and prediction of ADME-Tox properties. • From VS, the selected compounds were submitted to biological assays using the "DPPIV-Glo™ protease assay", as well as cytotoxicity tests were also carried out. • One promising compound (ZINC1572309) established interactions with important residues at the binding site of the target. • ZINC1572309 inhibited the DPP-4 activity, suggesting interesting biological effects at non-cytotoxic concentrations and it can be a promising candidate to inhibit DPP-4. [ABSTRACT FROM AUTHOR]