Discovery of tight-binding competitive inhibitors of dipeptidyl peptidase IV

Alonso, Isel Pascual; Valiente, Pedro A.; Valdés‐Tresanco, Mario E.; Arrebola, Yarini; García, Fabiola Almeida; Díaz, Lisset; García, Gabriela; Guirola, Osmany; Pastor, D.; Bergado, Gretchen; Sánchez, Belinda; Charlí, Jean-Louis

doi:10.1016/j.ijbiomac.2021.12.056

Cited by 3 publications

(1 citation statement)

References 58 publications

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“…In addition, Hermansyah et al found CH0002 as a potent DPP4 agent with low selectivity for DPP8 and DPP9 receptors using the VS in combination with the QSAR approach and artificial intelligence 19 . By the VS, the new non-peptides were found and evaluated as DPP4 inhibitors by Alonso et al 20 .…”

Section: Introductionmentioning

confidence: 99%

A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor

Zare,

Ataollahi,

Mardaneh

et al. 2024

Sci Rep

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DPP4 inhibitors can control glucose homeostasis by increasing the level of GLP-1 incretins hormone due to dipeptidase mimicking. Despite the potent effects of DPP4 inhibitors, these compounds cause unwanted toxicity attributable to their effect on other enzymes. As a result, it seems essential to find novel and DPP4 selective compounds. In this study, we introduce a potent and selective DPP4 inhibitor via structure-based virtual screening, molecular docking, molecular dynamics simulation, MM/PBSA calculations, DFT analysis, and ADMET profile. The screened compounds based on similarity with FDA-approved DPP4 inhibitors were docked towards the DPP4 enzyme. The compound with the highest docking score, ZINC000003015356, was selected. For further considerations, molecular docking studies were performed on selected ligands and FDA-approved drugs for DPP8 and DPP9 enzymes. Molecular dynamics simulation was run during 200 ns and the analysis of RMSD, RMSF, Rg, PCA, and hydrogen bonding were performed. The MD outputs showed stability of the ligand–protein complex compared to available drugs in the market. The total free binding energy obtained for the proposed DPP4 inhibitor was more negative than its co-crystal ligand (N7F). ZINC000003015356 confirmed the role of the five Lipinski rule and also, have low toxicity parameter according to properties. Finally, DFT calculations indicated that this compound is sufficiently soft.

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Section: Introductionmentioning

confidence: 99%

A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor

Zare,

Ataollahi,

Mardaneh

et al. 2024

Sci Rep

View full text Add to dashboard Cite

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Dipeptidyl peptidase IV: a multifunctional enzyme with implications in several pathologies including cancer

Sánchez

García

Sol

et al. 2023

Physical Sciences Reviews

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Ectopeptidases are particularly interesting due to their potential to regulate/dysregulate the peptide mediated signaling cellular pathways because the active site located to the extracellular space. Dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) is currently one of the ectopeptidases that has a great and complex influence on important physiological and pathological processes. Due to its influence on the immune system, type 2 diabetes mellitus, pulmonary pathologies, cardiovascular system, viral infections and cancer, DPP-IV is very attractive as a possible therapeutic target. However, its versatility makes such expectations very difficult. The aim of this work is to summarize relevant structural and functional aspects of DPP-IV and the role of this protein in several pathologies with special emphasis on cancer. DPP-IV role in cancer seems to depend on specific location, histologic type of tumour, tumour microenvironment, and presence/absence of molecules able to interact with DPP-IV. Because of DPP-IV controversial effects, generalizations are difficult and most of the time the role of DPP-IV must be analyzed case by case. However, new evidences in cell lines, animal models and clinical studies suggest that DPP-IV inhibitors open a promissory window through new therapeutic strategies against some cancers.

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Anti-cancer effects of sitagliptin, vildagliptin, and exendin-4 on triple-negative breast cancer cells via mitochondrial modulation

Jaiswal¹,

Tripathi²,

ASSAIYA³

et al. 2022

Biocell

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Triple-negative breast cancer (TNBC) cell line MDA-MB-231 is known for Warburg metabolism and defects in mitochondria. On the other hand, dipeptidyl peptidase-IV (DPP-IV) inhibitors such as sitagliptin and vildagliptin and GLP-1 agonist exendin-4 are known to improve mitochondrial functions as well as biogenesis, but no study has evaluated the influence of these drugs on mitochondrial biogenesis on metastatic breast cancer cell line. We have recently reported anticancer effects of 5-aminoimidazole-4-carboxamide riboside on MDA-MB-231 cells via activation of AMP-dependent kinase (AMPK), which activates the downstream transcription factors PGC-1α, PGC-1β, or FOXO1 for mitochondrial biogenesis; above-mentioned incretin-based therapies are also known to activate AMPK. This study evaluated the effects of sitagliptin, vildagliptin, and exendin-4 on MDA-MB-231 cells and the underlying changes in mitochondrial biogenesis, were examined. Treatment with sitagliptin (100 µM), vildagliptin (100 µM), and exendin-4 (10 nM) for 72 h to MDA-MB-231 cells led to a decrease in viability indicated by MTT assay, cell migration by scratch, and transwell migration assays, accompanied with marginal reduction in cell numbers along with the apoptotic appearance, the rate of apoptosis, and decreased lactate content in conditioned medium. These changes in the cancer phenotype were accompanied by an increase in the mitochondrial DNA to nuclear DNA ratio, increased MitoTracker green and red staining, and increased expression of transcription factors PGC-1α, NRF-1, NRF-2, TFAM, and HO-1. Pre-treatment of cells with these incretin-based drugs followed by 48 h treatment with 1 µM doxorubicin increased doxorubicin sensitivity as observed by a decrease in viability by MTT assay. Thus, sitagliptin, vildagliptin, and exendin-4 exert their beneficial effects on TNBC cells via an increase in mitochondrial biogenesis that helps to switch Warburg metabolism into anti-Warburg effect. Therapeutic response was in the order of: sitagliptin > vildagliptin > exendin-4.

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Discovery of tight-binding competitive inhibitors of dipeptidyl peptidase IV

Cited by 3 publications

References 58 publications

A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor

A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor

Dipeptidyl peptidase IV: a multifunctional enzyme with implications in several pathologies including cancer

Anti-cancer effects of sitagliptin, vildagliptin, and exendin-4 on triple-negative breast cancer cells via mitochondrial modulation

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