Molecular Docking, Pharmacophore Modeling and ADMET Profiling Study of Some Bioactive Phytochemicals from Indigofera Tinctoria as Potential Pparυ Inhibitors for the Treatment of Diabetes: An In-Silico Study

Abstract

In the pursuit of effective therapeutic strategies for diabetes mellitus (DM), peroxisome proliferator-activated receptor- PPARγ agonists have emerged as promising oral antidiabetic medications. However, the prevalence of adverse effects associated with many existing medications underscores the need for novel and safer alternatives. PPARγ, a key regulator of glucose and lipid homeostasis, is the target receptor for thiazolidinediones, a synthetic class of anti-diabetic medications. Given its pivotal role in the pathogenesis of Type II diabetes mellitus, drug discovery efforts have intensified to identify new compounds targeting PPARγ. This study employs a multi-faceted approach, integrating pharmacophore analysis, pharmacokinetic/toxicity evaluation, and in-silico molecular docking, to investigate the antidiabetic potential of phytoconstituents derived from Indigofera tinctoria (I. tinctoria) as potential PPARγ agonists. Molecular docking analysis of 21 selected phytoconstituents from I. tinctoria reveals that 18 exhibit superior binding affinity (ΔG ≥ -6.9 K cal/mol) and remarkably low inhibition constants (Ki ≤ 0.35 µM) compared to established thiazolidinediones—Pioglitazone and Rosiglitazone (ΔG ≤ 6.9 K cal/mol, Ki ≥ 8.74 µM).Among the top-performing compounds, namely Pseudosemiglabrin, Dehydrodeguelin, Apigenin, Tephrosin, Indirubin, and Indigo, further analysis through pharmacophore/ADMET profiling confirms their drug-likeness properties. These compounds adhere to Lipinski's Rule of 5, demonstrating favorable drug-like characteristics and exhibiting good oral bioavailability, as illustrated in the bioavailability radar. The findings suggest that naturally derived phytochemicals from I. tinctoria, particularly the identified compounds, hold promise as potential PPARγ agonists. These compounds, exhibiting robust in-silico characteristics, merit further experimental validation and may represent safer and more effective candidates for the development of novel antidiabetic agents.