Enzymatic release of dipeptidyl peptidase‐4 inhibitors (gliptins) from pigeon pea (
            Cajanus cajan
            ) nutrient reservoir proteins: In silico and in vitro assessments

Background: Dipeptidyl peptidase-4 (DPP4) is an enzyme responsible for inactivating the hormone incretin, which potentiates insulin secretion andglucagon inhibition; inhibitors of DPP4 are used as therapeutic drugs for type-2 diabetes.Objective: In this study, we evaluated potential DPP4 inhibitors from the Indonesian Medicinal Plants Database using an in silico approach.Methods: A ligand-based pharmacophore model was used for screening the database using LigandScout 4.2. This model was validated using severalparameters of enrichment metrics, including receiver operating characteristics, area under curve (AUC), and enrichment factor (EF). Hit compoundswere also docked with DPP4 to calculate the free binding energy and analyze the interaction between the ligand and DPP4. In addition, bioavailabilityand medicinal chemistry predictions were performed for the hit compounds.Results: The best pharmacophore model demonstrated AUC100% and EF1% values of 0.82 and 33.8, respectively. The pharmacophore features of themodel included hydrogen bond donors, hydrogen bonds, hydrophobic interactions, and positive ionization areas. Based on our results of virtualscreening and molecular docking, six hit compounds were ultimately identified, namely, L-noradrenaline, octopamine, Nb-demethylechitamine, alliin,isoalliin, and subaphylline.Conclusion: Collectively, our findings indicate that subaphylline is the most promising compound for further studies, including in vitro and in vivoexperiments and those focused on molecular dynamics and structural modification.

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α-Amylase and dipeptidyl peptidase-4 (DPP-4) inhibitory effects of Melicope latifolia bark extracts and identification of bioactive constituents using in vitro and in silico approaches

Pharmaceutical Biology ◽

10.1080/13880209.2021.1948065 ◽

2021 ◽

Vol 59 (1) ◽

pp. 964-973

Author(s):

Alexandra Quek ◽

Nur Kartinee Kassim ◽

Pei Cee Lim ◽

Dai Chuan Tan ◽

Muhammad Alif Mohammad Latif ◽

...

Keyword(s):

In Silico ◽

Dipeptidyl Peptidase ◽

Inhibitory Effects ◽

Bioactive Constituents ◽

Dipeptidyl Peptidase 4

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Dipeptidyl peptidase-4 inhibitor protects against non-alcoholic steatohepatitis in mice by targeting TRAIL receptor-mediated lipoapoptosis via modulating hepatic dipeptidyl peptidase-4 expression

Scientific Reports ◽

10.1038/s41598-020-75288-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Minyoung Lee ◽

Eugene Shin ◽

Jaehyun Bae ◽

Yongin Cho ◽

Ji-Yeon Lee ◽

...

Keyword(s):

Molecular Mechanisms ◽

Dipeptidyl Peptidase ◽

Trail Receptor ◽

Dipeptidyl Peptidase 4 ◽

Alcoholic Steatohepatitis ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Group 2 ◽

Induced Apoptosis

Abstract Dipeptidyl peptidase-4 inhibitors (DPP4i) are antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP4). DPP4 is ubiquitously expressed, and its hepatic DPP4 expression is upregulated under non-alcoholic steatohepatitis (NASH) conditions. We investigated the effect of DPP4i treatment on NASH pathogenesis, as well as its potential underlying molecular mechanisms. Mice were randomly divided into three groups: Group 1, chow-fed mice treated with vehicle for 20 weeks; Group 2, high-fat, high-fructose, and high-cholesterol Amylin liver NASH (AMLN) diet-fed mice treated with vehicle for 20 weeks; Group 3, AMLN diet-fed mice treated with vehicle for the first 10 weeks, followed by the DPP4i teneligliptin (20 mg/kg/day) for additional 10 weeks. DPP4i administration reduced serum liver enzyme and hepatic triglyceride levels and markedly improved hepatic steatosis and fibrosis in the AMLN diet-induced NASH model. In vivo, NASH alleviation significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and downregulated hepatic DPP4 expression. In vitro, DPP4i treatment significantly decreased the markers of TRAIL receptor-mediated lipoapoptosis and suppressed DPP4 expression in palmitate-treated hepatocytes. In conclusion, DPP4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly by modulating hepatic DPP4 expression.

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The Nonglycemic Actions of Dipeptidyl Peptidase-4 Inhibitors

BioMed Research International ◽

10.1155/2014/368703 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 29

Author(s):

Na-Hyung Kim ◽

Taeyang Yu ◽

Dae Ho Lee

Keyword(s):

Randomized Clinical Trials ◽

Cardiovascular Effects ◽

Dipeptidyl Peptidase ◽

Protective Effects ◽

Dipeptidyl Peptidase 4 ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Glucagon Like Peptide 1 ◽

Stimulation Of

A cell surface serine protease, dipeptidyl peptidase 4 (DPP-4), cleaves dipeptide from peptides containing proline or alanine in the N-terminal penultimate position. Two important incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), enhance meal-stimulated insulin secretion from pancreaticβ-cells, but are inactivated by DPP-4. Diabetes and hyperglycemia increase the DPP-4 protein level and enzymatic activity in blood and tissues. In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects. Studies have shown that DPP-4 itself is involved in the inflammatory signaling pathway, the stimulation of vascular smooth cell proliferation, and the stimulation of oxidative stress in various cells. DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in bothin vitroandin vivoexperiments. However, in recent randomized clinical trials, DPP-4 inhibitor therapy in high risk patients with type 2 diabetes did not show cardiovascular protective effects. Some concerns on the actions of DPP-4 inhibitor include sympathetic activation and neuropeptide Y-mediated vascular responses. Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor.

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Combined Ligand-Based and Structure-Based Virtual Screening Approach for Identification of New Dipeptidyl Peptidase 4 Inhibitors

Current Drug Discovery Technologies ◽

10.2174/1570163815666180926111558 ◽

2019 ◽

Vol 16 (4) ◽

pp. 426-436

Author(s):

Jagatkumar Upadhyay ◽

Anuradha Gajjar ◽

Bhanubhai N. Suhagia

Keyword(s):

Amino Acid ◽

Virtual Screening ◽

Pharmacophore Model ◽

Dipeptidyl Peptidase ◽

Receiver Operating Curve ◽

Scoring Method ◽

Dipeptidyl Peptidase 4 ◽

Starting Point ◽

Dipeptidyl Peptidase 4 Inhibitors

Background: Dipeptidyl Peptidase 4 (DPP 4) enzyme cleaves an incretin-based glucoregulatory hormone Glucagon Like Peptide -1 from N-terminal where penultimate amino acid is either alanine or proline. Several DPP 4 inhibitors, “gliptins”, are approved for the management of Type 2 Diabetes or are under clinical trial. In the present study, combined pharmacophore and docking-based virtual screening protocol were used for the identification of new hits from the Specs Database, which would inhibit DPP 4. Methods: The entire computational studies were performed using the Discovery Studio v. 4.1 software package, Pipeline Pilot v. 9.2 (Accelrys Inc.) and FRED v. 2.2.5 (OpenEye Scientific Software). Common feature pharmacophore model was generated from known DPP 4 inhibitors and validated by Receiver Operating curve analysis and GH-scoring method. Database search of Specs commercial database was performed using validated pharmacophore. Hits obtained from pharmacophore search were further docked into the binding site of DPP 4. Based on the analysis of docked poses of hits, 10 compounds were selected for in- vitro DPP 4 enzyme inhibition assay. Results: Based on docking studies, virtual hits were predicted to form interaction with essential amino acid residues of DPP 4 and have an almost similar binding orientation as that of the reference molecule. Three compounds having Specs database ID- AN-465/42837213, AP-064/42049348 and AN- 465/43369427 were found to inhibit DPP 4 enzyme moderately. Conclusion: The present study demonstrates a successful utilization of in-silico tools in the identification of new DPP 4 inhibitor, which can serve as a starting point for the development of novel DPP 4 inhibitors.

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