In silico identification of potential drug compound against Peroxisome proliferator-activated receptor-gamma by virtual screening and toxicity studies for the treatment of Diabetic Nephropathy

Abstract

Diabetic Nephropathy is a serious complication of diabetes mellitus. Current therapeutic strategies of Diabetic Nephropathy are based on control of modifiable risks like hypertension, glucose levels, and dyslipidemia. Peroxisome proliferator activated receptor-gamma (PPAR-γ) is implicated in several metabolic syndromes including Diabetic Nephropathy, besides obesity, insulin insensitivity, dislipidemia, inflammation, and hypertension. In the present study, virtual screening of 617 compounds from two different public databases was done against PPAR-γ with an objective to find a possible lead compound. Two softwares, PyRx and iGEMDOCK, were used to achieve the docking accuracy in order to avoid loss of candidate compounds. Rosiglitazone (used to treat Diabetic Nephropathy) was taken as the standard compound. A total of 30 compounds with good binding affinity with PPAR-γ were selected for further filtering, on the basis of absorption, distribution, metabolism, excretion, and toxicity (ADMET). The interaction profiling of these 30 compounds, showed a minimum of one and maximum of three interactions with reference to rosiglitazone (SER-289, HIS-449, HIS-323, TYR-473). The fulfilling of ADMET analysis criteria of 30 compounds led to the selection of four compounds (ZINC ID 00181552, 00276456, 00298314, 00448009). Molecular dynamics simulation of these lead compounds in complex with PPAR-γ revealed that three of the four compounds formed a stable complex in the ligand-binding pocket of PPAR-γ during 20-ns simulation. Hence, these three (ZINC ID 00181552, 00276456, 00298314) of the four compounds are potential candidates for experimental validation of biological activity against PPAR-γ in future drug discovery studies.

Keywords:

• ADMET analysis
• Diabetic Nephropathy
• interaction profile
• PPAR-γ
• rosiglitazone

Acknowledgment

The facility provided by Bioinformatics Centre, National Institute of Immunology is gratefully acknowledged.