Benzo[4,5]thieno[2,3‐<i>d</i>]pyrimidine phthalimide derivative, one of the rare noncompetitive inhibitors of dipeptidyl peptidase‐4

Tomovic, Katarina; Ilić, Budimir S.; Miljković, Marija; Dimov, Stefan; Yancheva, Denitsa; Kojić, Milan; Mavrova, Anelia Ts.; Kocić, Gordana; Šmelcerović, Andrija

doi:10.1002/ardp.201900238

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…Most of the DPP4 inhibitors in the market are competitive inhibitors, e. g., alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin [1,16,23]. On the contrary, several inhibitors were reported as noncompetitive inhibitors in vitro [21,24], which indicated the availability of allosteric sites in the DPP4 binding pocket [24].…”

Section: Discussionmentioning

confidence: 99%

Molecular Dynamics Simulations of the Caffeic Acid Interactions to Dipeptidyl Peptidase Iv

Istyastono

Riswanto

2022

Int J App Pharm

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Objective: The research presented in this article aimed to examine the applicability of a recently published software PyPLIF HIPPOS to identify the interactions hotspots between dipeptidyl peptidase IV (DPP4) and its inhibitor caffeic acid during molecular dynamics (MD) simulations. Methods: Caffeic acid was docked to the binding pocket of DPP4 followed by 50 ns MD simulations, during which snapshots were taken every 10 ps. The molecular docking and the MD simulations were performed in YASARA-Structure 21.12.19. The snapshots were analyzed using the MM/PBSA analysis in YASARA-Structure and PyPLIF HIPPOS to calculate the binding energy (BE) and the caffeic acid-DPP4 interactions hotspots, respectively. Results: The 50 ns MD simulations of DPP4-caffeic acid had converged since the early stage of the simulations. The BE and the RMSD values of the ligand movement indicated a probable DPP4 allosteric site. PyPLIF HIPPOS identified 15 interacting DPP4 residues to caffeic acid. The residues interacting with caffeic acid in more than 10% snapshots of the MD simulations were Ser59, Arg61, Glu206, and Phe357. The binding residues Ser59 and Arg61 were suggested to be part of the plausible DPP4 allosteric site. Conclusion: PyPLIF HIPPOS serves as a valuable complement to the MM/PBSA method in the examination of enzyme-inhibitor interactions.

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Section: Discussionmentioning

confidence: 99%

Molecular Dynamics Simulations of the Caffeic Acid Interactions to Dipeptidyl Peptidase Iv

Istyastono

Riswanto

2022

Int J App Pharm

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“…These results suggested that caffeic acid started escaping the active site at the simulation time of 1.5 ns to occupy more stable interactions in the plausible sites. Hence, caffeic acid might never interacte stably in the DPP-4 active site and might be a non-competitive inhibitor of DPP-4 as several non-competitive inhibitors, as previously reported [40][41][42].…”

Section: Molecular Dynamics and Interaction Hotspot Identifications O...mentioning

confidence: 59%

“…Tables 1 and 2 show that throughout the simulation, caffeic acid interacted with amino acid residues of Lys463 (47.50%) and Trp62 (12.57%) dominantly. Our investigations found that Lys463 forming an hydrophobic interaction and Trp62 forming an aromatic edge-to-face interaction were considered as the interaction hotspots located in the DPP-4 From this simulation time, it could be seen that the RMSD LigMove value increased gradually along the simulation time until it reached 3.0 ns with an RMSD value of 18.158 Å while caffeic acid was no longer interacting with amino acid residues in the active side, revealing the availability of allosteric sites [40]. Even though there was a decreasing RMSD value reaching 9.209 Å at a simulation time of 5.7 ns, caffeic acid remained interacted in a plausible allosteric site.…”

Section: Molecular Dynamics and Interaction Hotspot Identifications O...mentioning

confidence: 98%

Caffeic Acid in Spent Coffee Grounds as a Dual Inhibitor for MMP-9 and DPP-4 Enzymes

Istyastono,

Yuniarti,

Prasasty

et al. 2023

Molecules

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Type 2 diabetes mellitus and diabetic foot ulcers remain serious worldwide health problems. Caffeic acid is one of the natural products that has been experimentally proven to have diverse pharmacological properties. This study aimed to assess the inhibitory activity of caffeic acid and ethanolic extract of spent coffee grounds targeting DPP-4 and MMP-9 enzymes and evaluate the molecular interactions through 50-ns molecular dynamics simulations. This study also introduced our new version of PyPLIF HIPPOS, PyPLIF HIPPOS 0.2.0, which allowed us to identify protein–ligand interaction fingerprints and interaction hotspots resulting from molecular dynamics simulations. Our findings revealed that caffeic acid inhibited the DPP-4 and MMP-9 activity with an IC50 of 158.19 ± 11.30 µM and 88.99 ± 3.35 µM while ethanolic extract of spent coffee grounds exhibited an IC50 of 227.87 ± 23.80 µg/100 µL and 81.24 ± 6.46 µg/100 µL, respectively. Molecular dynamics simulations showed that caffeic acid interacted in the plausible allosteric sites of DPP-4 and in the active site of MMP-9. PyPLIF HIPPOS 0.2.0 identified amino acid residues interacting more than 10% throughout the simulation, which were Lys463 and Trp62 in the plausible allosteric site of DPP-4 and His226 in the active site of MMP-9.

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Recent Medicinal Chemistry Approach for the Development of Dipeptidyl Peptidase IV Inhibitors

Shah¹,

Modi

Trivedi³

2021

CMC

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Background: Diabetes, a metabolic disease occurs due to decrease or no effect of insulin on blood glucose level. Current oral medication stimulates insulin release, increase glucose absorption and its utilization as well decrease hepatic glucose output. Two major incretin hormones like Glucose dependent insulinotropic polypeptide (GIP) and glucagon like peptide – 1 (GLP -1) stimulate insulin release after meal but their action is inhibited by enzyme dipeptidyl peptidase- IV. Objective: The activity of endogenous GLP-1 and GIP prolong and extend with DPP IV inhibitors which are responsible for stimulation of insulin secretion and regulate blood glucose level. DPP IV inhibitors have shown effectiveness and endurability with neutral effect on weight as well as less chances of hypoglycemia in management of type 2 diabetes. These journeys have been started from Sitagliptin (marketed in 2006) to Evogliptin (marketed in 2015, Korea). Conclusion: Treatment of type 2 diabetes includes lifestyle changes, oral medications, and insulin. Newer and superior therapies are required than presently prescribed drugs. Various heterocyclic derivatives have been tried but due to masking of DASH proteins, CYP enzymes and hERG channel, they showed side effects. Based on these, study has been focused on the development of safe, influential, selective and long-lasting inhibitors of DPP IV.

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Benzo[4,5]thieno[2,3‐d]pyrimidine phthalimide derivative, one of the rare noncompetitive inhibitors of dipeptidyl peptidase‐4

Cited by 4 publications

References 26 publications

Molecular Dynamics Simulations of the Caffeic Acid Interactions to Dipeptidyl Peptidase Iv

Molecular Dynamics Simulations of the Caffeic Acid Interactions to Dipeptidyl Peptidase Iv

Caffeic Acid in Spent Coffee Grounds as a Dual Inhibitor for MMP-9 and DPP-4 Enzymes

Recent Medicinal Chemistry Approach for the Development of Dipeptidyl Peptidase IV Inhibitors

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