Repurposing of FDA-approved NSAIDs for DPP-4 inhibition as an alternative for diabetes mellitus treatment: Computational and in vitro study

Veera C.S.R. Chittepu, Poonam Kalhotra, Tzayhri Osorio-Gallardo, Tzayhri Gallardo-Velázquez, Guillermo Osorio-Revilla

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

A drug repurposing strategy could be a potential approach to overcoming the economic costs for diabetes mellitus (DM) treatment incurred by most countries. DM has emerged as a global epidemic, and an increase in the outbreak has led developing countries like Mexico, India, and China to recommend a prevention method as an alternative proposed by their respective healthcare sectors. Incretin-based therapy has been successful in treating diabetes mellitus, and inhibitors like sitagliptin, vildagliptin, saxagliptin, and alogliptin belong to this category. As of now, drug repurposing strategies have not been used to identify existing therapeutics that can become dipeptidyl peptidase-4 (DPP-4) inhibitors. Hence, this work presents the use of bioinformatics tools like the Activity Atlas model, flexible molecular docking simulations, and three-dimensional reference interaction site model (3D-RISM) calculations to assist in repurposing Food and Drug Administration (FDA)-approved drugs into specific nonsteroidal anti-inflammatory medications such as DPP-4 inhibitors. Initially, the Activity Atlas model was constructed based on the top scoring DPP-4 inhibitors, and then the model was used to understand features of nonsteroidal anti-inflammatory drugs (NSAIDs) as a function of electrostatic, hydrophobic, and active shape features of DPP-4 inhibition. The FlexX algorithm was used to infer protein–ligand interacting residues, and binding energy, to predict potential draggability towards the DPP-4 mechanism of action. 3D-RISM calculations on piroxicam-bound DPP-4 were used to understand the stability of water molecules at the active site. Finally, piroxicam was chosen as the repurposing drug to become a new DPP-4 inhibitor and validated experimentally using fluorescence spectroscopy assay. These findings are novel and provide new insights into the role of piroxicam as a new lead to inhibit DPP-4 and, taking into consideration the biological half-life of piroxicam, it can be proposed as a possible therapeutic strategy for treating diabetes mellitus.

Original languageEnglish
Article number238
JournalPharmaceutics
Volume11
Issue number5
DOIs
StatePublished - May 2019

Fingerprint

Dipeptidyl-Peptidase IV Inhibitors
Dipeptidyl Peptidase 4
Piroxicam
Drug Repositioning
United States Food and Drug Administration
Diabetes Mellitus
Anti-Inflammatory Agents
Atlases
Pharmaceutical Preparations
Molecular Docking Simulation
Incretins
Health Care Sector
Fluorescence Spectrometry
Mexico
Computational Biology
Static Electricity
Developing Countries
Disease Outbreaks
Half-Life
India

Keywords

  • Diabetes mellitus
  • Dipeptidyl peptidase-4 inhibitors
  • DPP-4
  • Drug repurposing
  • Nonsteroidal anti-inflammatory drugs
  • NSAIDs

Cite this

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title = "Repurposing of FDA-approved NSAIDs for DPP-4 inhibition as an alternative for diabetes mellitus treatment: Computational and in vitro study",
abstract = "A drug repurposing strategy could be a potential approach to overcoming the economic costs for diabetes mellitus (DM) treatment incurred by most countries. DM has emerged as a global epidemic, and an increase in the outbreak has led developing countries like Mexico, India, and China to recommend a prevention method as an alternative proposed by their respective healthcare sectors. Incretin-based therapy has been successful in treating diabetes mellitus, and inhibitors like sitagliptin, vildagliptin, saxagliptin, and alogliptin belong to this category. As of now, drug repurposing strategies have not been used to identify existing therapeutics that can become dipeptidyl peptidase-4 (DPP-4) inhibitors. Hence, this work presents the use of bioinformatics tools like the Activity Atlas model, flexible molecular docking simulations, and three-dimensional reference interaction site model (3D-RISM) calculations to assist in repurposing Food and Drug Administration (FDA)-approved drugs into specific nonsteroidal anti-inflammatory medications such as DPP-4 inhibitors. Initially, the Activity Atlas model was constructed based on the top scoring DPP-4 inhibitors, and then the model was used to understand features of nonsteroidal anti-inflammatory drugs (NSAIDs) as a function of electrostatic, hydrophobic, and active shape features of DPP-4 inhibition. The FlexX algorithm was used to infer protein–ligand interacting residues, and binding energy, to predict potential draggability towards the DPP-4 mechanism of action. 3D-RISM calculations on piroxicam-bound DPP-4 were used to understand the stability of water molecules at the active site. Finally, piroxicam was chosen as the repurposing drug to become a new DPP-4 inhibitor and validated experimentally using fluorescence spectroscopy assay. These findings are novel and provide new insights into the role of piroxicam as a new lead to inhibit DPP-4 and, taking into consideration the biological half-life of piroxicam, it can be proposed as a possible therapeutic strategy for treating diabetes mellitus.",
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Repurposing of FDA-approved NSAIDs for DPP-4 inhibition as an alternative for diabetes mellitus treatment : Computational and in vitro study. / Chittepu, Veera C.S.R.; Kalhotra, Poonam; Osorio-Gallardo, Tzayhri; Gallardo-Velázquez, Tzayhri; Osorio-Revilla, Guillermo.

In: Pharmaceutics, Vol. 11, No. 5, 238, 05.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Repurposing of FDA-approved NSAIDs for DPP-4 inhibition as an alternative for diabetes mellitus treatment

T2 - Computational and in vitro study

AU - Chittepu, Veera C.S.R.

AU - Kalhotra, Poonam

AU - Osorio-Gallardo, Tzayhri

AU - Gallardo-Velázquez, Tzayhri

AU - Osorio-Revilla, Guillermo

PY - 2019/5

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AB - A drug repurposing strategy could be a potential approach to overcoming the economic costs for diabetes mellitus (DM) treatment incurred by most countries. DM has emerged as a global epidemic, and an increase in the outbreak has led developing countries like Mexico, India, and China to recommend a prevention method as an alternative proposed by their respective healthcare sectors. Incretin-based therapy has been successful in treating diabetes mellitus, and inhibitors like sitagliptin, vildagliptin, saxagliptin, and alogliptin belong to this category. As of now, drug repurposing strategies have not been used to identify existing therapeutics that can become dipeptidyl peptidase-4 (DPP-4) inhibitors. Hence, this work presents the use of bioinformatics tools like the Activity Atlas model, flexible molecular docking simulations, and three-dimensional reference interaction site model (3D-RISM) calculations to assist in repurposing Food and Drug Administration (FDA)-approved drugs into specific nonsteroidal anti-inflammatory medications such as DPP-4 inhibitors. Initially, the Activity Atlas model was constructed based on the top scoring DPP-4 inhibitors, and then the model was used to understand features of nonsteroidal anti-inflammatory drugs (NSAIDs) as a function of electrostatic, hydrophobic, and active shape features of DPP-4 inhibition. The FlexX algorithm was used to infer protein–ligand interacting residues, and binding energy, to predict potential draggability towards the DPP-4 mechanism of action. 3D-RISM calculations on piroxicam-bound DPP-4 were used to understand the stability of water molecules at the active site. Finally, piroxicam was chosen as the repurposing drug to become a new DPP-4 inhibitor and validated experimentally using fluorescence spectroscopy assay. These findings are novel and provide new insights into the role of piroxicam as a new lead to inhibit DPP-4 and, taking into consideration the biological half-life of piroxicam, it can be proposed as a possible therapeutic strategy for treating diabetes mellitus.

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