ABSTRACT
Mycobacterium tuberculosis (Mtb) is a notorious pathogen that causes one of the highest mortalities globally. Due to a pressing demand to identify novel therapeutic alternatives, the present study aims to focus on screening the putative drug targets and prioritizing their role in antibacterial drug development. The most vital proteins involved in the Biotin biosynthesis pathway and the Lipoarabinomannan (LAM) pathway such as biotin synthase (bioB) and alpha-(1->6)-mannopyranosyltransferase A (mptA) respectively, along with other essential virulence proteins of Mtb were selected as drug targets. Among these, the ones without native structures were modelled and validated using standard bioinformatics tools. Further, the interactions were performed with naturally available lead molecules present in selected mushroom species such as Agaricus bisporus, Pleurotus djamor, Hypsizygus ulmarius. Through Gas Chromatography-Mass Spectrometry (GC-MS), 15 bioactive compounds from the methanolic extract of mushrooms were identified. Further, 4 were selected based on drug-likeness and pharmacokinetic screening for molecular docking analysis against our prioritized targets wherein Benz[e]azulene from Pleurotus djamor illustrated a good binding affinity with a LF rank score of -9.036 kcal mol -1 against nuoM (NADH quinone oxidoreductase subunit M) and could be used as a prospective candidate in order to combat Tuberculosis (TB). Furthermore, the stability of the complex are validated using MD Simulations and subsequently, the binding free energy was calculated using MM-GBSA analysis. Thus, the current in silico analysis suggests a promising role of compounds extracted from mushrooms in tackling the TB burden.Communicated by Ramaswamy H. Sarma.
ABSTRACT
Toll like receptors (TLRs), a class of conserved immune molecules are crucially involved in initiating innate immune response to infection. TLR activation and subsequent inflammation are linked to pathogenesis of many brain disorders. Preliminary studies indicate a possible role of TLR-driven immuno-inflammatory responses in schizophrenia. However, gene expression data of TLRs in drug-naïve as well as antipsychotic treated patients diagnosed with schizophrenia are albeit limited. In this study, expression profile of TLR3 and TLR4 genes in peripheral blood mononuclear cells (PBMCs) was compared between drug-naïve patients diagnosed with schizophrenia (N = 31) and healthy controls (N = 30). In addition, the pattern of expression of TLR3 and TLR4 genes were also examined after three months of antipsychotic medication in patients. Compared to healthy controls, gene expression levels of only TLR4 (F = 3.87, p = 0.05, ηp2 = 0.06), not TLR3 (F = 0.17, p = 0.71, ηp2 = 0.003) was significantly up-regulated in drug-naïve patients. The changes in the levels of gene expression of TLR3 (t = 0.09, p = 0.93, d = 0.02) and TLR4 (t = 0.29, p = 0.77, d = 0.06) before and after antipsychotic medication were not found to be statistically significant. This finding suggests possible contribution of TLR4 in immunopathogenetic pathway of schizophrenia.
