Identification of antidiabetic leads using in-silico screening, molecular dynamics simulation, and biological...

Type II diabetes mellitus is a major endocrine disorder characterized by persistent hyperglycemia, insulin resistance, and dysregulation in glucose uptake by the cells. Peroxisome proliferator-activated receptor-γ (PPARγ) plays a significant role in the regulation of glucose and lipid metabolism as well as in post-diabetic inflammatory response. Therefore, PPARγ activators seem to be the drugs of choice. In the present work, structure-based virtual screening approach was employed to find newer compounds as PPARγ agonist. The ChemDiv library (freely available) of compounds was used for hierarchical virtual screening; the hits obtained were further evaluated based on in silico predicted binding energy and toxicity predictions. The structure-based approach yielded 18 high-affinity, stably binding hits, from which 08 hits (Sn1-Sn8) were predicted to be non-toxic. Further, in vitro exploration of the anti-diabetic as well as PPARγ agonistic potential was carried out on eight (08) ligands obtained from in silico scrutiny, using various in vitro assays. The synthesized quinazolinedione based compound (Sn9) was also evaluated similarly for exploration of its lead-likeness as PPARγ agonistic anti-diabetic candidate. Compounds Sn7 and Sn8 showed adequate glucose uptake by the cells, anti-adipogenicity, and PPARγ binding, while Sn4 and Sn9 showed moderate potential in the same examination. Safety profiles of these compounds on 3T3-L1 and C2C12 cells were also established. The in vitro studies suggested that imidazopyridine (present in Sn4, Sn8) and quinazolinedione (present in Sn7 and Sn9) have much potential against T2DM. Sn8 was found to be the best candidate, and it also demonstrated a stable trajectory and interaction profile in simulated physiological environment. The study confirms the lead-like potential of compound Sn8, and supports the exploration of imidazopyridine and quinazolinedione ring systems for further development of PPARγ agonistic lead compounds in the anti-diabetic arena.