A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor.
Sci Rep
; 14(1): 7749, 2024 04 02.
Article
en En
| MEDLINE
| ID: mdl-38565703
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Inhibidores de la Dipeptidil-Peptidasa IV
/
Simulación de Dinámica Molecular
Idioma:
En
Revista:
Sci Rep
Año:
2024
Tipo del documento:
Article
País de afiliación:
Irán
Pais de publicación:
Reino Unido