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Dipeptidyl Peptidase-IV Blockers Potently Inhibit Monoglyceride Lipase: Investigation By Docking Studies And In Vitro Bioassay

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Abstract

Monoglyceride lipase (MGL) is an important enzyme that plays a critical role in lipolysis and release of free fatty acids from triacylglycerides stores. High levels of circulating free fatty acids impair insulin sensitivity and induce inflammation. Several studies have shown that dipeptidyl peptidase-IV (DPP-IV) inhibitors can improve insulin sensitivity and suppress inflammatory response by unknown mechanism. Structural similarities between DPP-IV and MGL prompted us to propose that DPP-IV inhibitors can block MGL. Accordingly, we evaluated 6 known DPP-IV inhibitors as potential MGL blockers using docking experiments and in vitro bioassay. All tested compounds were successfully docked into the catalytic site of MGL. Vildagliptin, sitagliptin, omarigliptin and trelagliptin illustrated significant anti-MGL inhibitory percentages at 10 µM, while gosogliptin and saxagliptin were rather potent MGL inhibitors with IC50 values of 6.9 nM and 136.2 nM, respectively. This is the first time to report potent inhibitory effects of DPP-IV inhibitors against MGL. This finding provide evidence for a new mechanism by which DPP-IV inhibitors improve insulin sensitivity and suppress inflammation response independent of incretin hormones pathway.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank Research and Deanship of Scientific Research at the University of Jordan for sponsoring this project.

Author contributions

DA: Investigation, Formal analysis, Review & Editing. LAD: Formal analysis, Review & Editing. MOT: Conceptualization, Methodology, Supervision, Investigation, Resources, Writing, Review & Editing.

Funding

This work was supported by the Research and Deanship of Scientific Research at the University of Jordan [grant number 140/2021-2022].

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Queen Rania St, Amman, 11942, Jordan

    Dania Alkabbani, Lina A. Dahabiyeh & Mutasem O. Taha

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  1. Dania Alkabbani
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  2. Lina A. Dahabiyeh
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  3. Mutasem O. Taha
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Correspondence to Mutasem O. Taha.

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Alkabbani, D., Dahabiyeh, L.A. & Taha, M.O. Dipeptidyl Peptidase-IV Blockers Potently Inhibit Monoglyceride Lipase: Investigation By Docking Studies And In Vitro Bioassay. Med Chem Res 32, 165–175 (2023). https://doi.org/10.1007/s00044-022-02998-5

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