Exploring the rare variants associated with Type 2 Diabetes Mellitus in Indian population and its disease-drug association studies: an approach.

The diversified eating habits and religious culture of Indian population may be one of the reasons they largely contribute to the global diabetes burden. In the present investigation, an approach was carried out to explore hub genes in the Indian population with Type 2 Diabetes Mellitus (T2DM) that are scantily reported in the GWAS catalogue and probable potential anti-diabetic drugs from plants. This computational approach unwrapped LEP (leptin) as the hub gene among 170 genes analyzed with 14 non-synonymous single nucleotide polymorphisms (nsSNPs) with MAF < 0.01. The mutation of the LEP gene leads to a decrease in leptin concentration, which increases the risk of obesity and T2DM. According to the DUET webserver, 11 of 14 mutations examined were found to destabilize the LEP protein. Among 14, four barely reported LEP variants rs781301976 (I45N), rs776443424 (S52F), rs200915360 (D76Y), and rs1191666811 (D162N) were unzipped to be associated with T2DM, which may be the probable potential drug targets. The virtual screening revealed Vescalagin as having the highest binding energy among 336 natural compounds. Molecular docking of Vescalagin depicted higher binding energy (-9.0 kcal/mol) against mutated LEP [rs200915360 (D76Y)] compared to wild (-8.9 kcal/mol) and LEP-Metformin complexes. The trajectory analysis of MD simulations revealed that Vescalagin was more effective than Metformin in stabilizing the system. The present study suggests that the associations of the investigated nsSNPs in LEP [rs200915360 (D76Y)] and others can be key factors in the predominant role of T2DM morbidity in the Indian population that can be used as potential markers and drug targets for T2DM therapeutics.Communicated by Ramaswamy H. Sarma.