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Open AccessArticle

Repurposing of FDA-Approved NSAIDs for DPP-4 Inhibition as an Alternative for Diabetes Mellitus Treatment: Computational and in Vitro Study

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Departamento de Ingenieria Bioquimica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Av. Wilfrido Massieu S/N, Col. Unidad Profesional Adolfo Lopez Mateos, Zacatenco, C.P. Ciudad de Mexico 07738, Mexico
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Departamento de Biofisica, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Prolongacion de Carpio y Plan de Ayala S/N, Col. Santo Tomas, CP. Ciudad de Mexico 11340, Mexico
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Departamento de Microbiologia e Immunologia, Facultad de Medicina Vetererneria Y Zootecnia, Universidad Nacional Autonoma de Mexico, Av. Universidad #3000, Delegacion Coyoacan, Col. Ciudad Universitaria, Ciudad de Mexico 04510, Mexico
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Author to whom correspondence should be addressed.
Pharmaceutics 2019, 11(5), 238; https://doi.org/10.3390/pharmaceutics11050238
Received: 8 March 2019 / Revised: 8 May 2019 / Accepted: 14 May 2019 / Published: 17 May 2019
(This article belongs to the Special Issue Computational Drug Repurposing)
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. View Full-Text
Keywords: drug repurposing; nonsteroidal anti-inflammatory drugs; NSAIDs; diabetes mellitus; dipeptidyl peptidase-4 inhibitors; DPP-4 drug repurposing; nonsteroidal anti-inflammatory drugs; NSAIDs; diabetes mellitus; dipeptidyl peptidase-4 inhibitors; DPP-4
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Chittepu, V.C.S.R.; Kalhotra, P.; Osorio-Gallardo, T.; Gallardo-Velázquez, T.; Osorio-Revilla, G. Repurposing of FDA-Approved NSAIDs for DPP-4 Inhibition as an Alternative for Diabetes Mellitus Treatment: Computational and in Vitro Study. Pharmaceutics 2019, 11, 238.

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