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AbstractThe 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 in-silicoapproach 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

AbstractSagS sensor regulator plays a vital role in biofilm development of Pseudomonas aeruginosawhich subsequently makes the cells more tolerant to various antimicrobials. The multidrug resistance (MDR) issue has risen substantially in recent years and is considered a global threat. Therefore, alternative compounds should be unearthed immediately to address the issues related to P. aeruginosadrug resistance for which SagS could be a candidate. The present study is an attempt to screen natural anti-biofilm compounds as the potent inhibitors of SagS. Twenty natural anti-biofilm/quorum sensing inhibiting compounds were retrieved from various literatures with significant inhibitory effects against P. aeruginosabiofilm from in-vitroexperiments which were screened using various pharmacokinetic parameters. The screened and three standard drugs were docked against SagS-HisKA using AutoDock 4.2 tool, which were further analysed by MD simulations to understand the binding mode of compounds and dynamic behaviour of the complexes. Two potential anti-biofilm natural compounds, pinocembrin with binding affinity (-7.19 kcal/mol), vestitol (-7.18 kcal/mol) and the standard drug ceftazidime (-8.89 kcal/mol) were selected based on filtered parameters and better binding affinity. The trajectory analysis of MD simulations reflected Pinocembrin in stabilizing the system compared to ceftazidime. The existing reports state that the natural products represent promising source of therapy with least or almost nil adverse effect compared to synthetic drugs which is well collated with our in-silico findings. This investigation can save both time and cost required for in-vitroand in-vivoanalysis for designing of a novel anti-biofilm agent against P. aeruginosabiofilm-associated infections.Communicated by Ramaswamy H. Sarma