Structural analysis and molecular docking of potential ligands with chorismate synthase of Listeria monocytogenes: A novel antibacterial drug target.

Listeriosis, in particular that caused by Listeria monocytogenes, is a major foodborne pathogen, and its control is becoming difficult because of widespread emergence of drug resistance strains. Chorismate synthase (CS), an essential enzyme of shikimate pathway present only in bacteria, fungi, plant and some apicomplexan parasites, is a validated potential antimicrobial drug target. Antimicrobial development through the elucidation of essential structural features of the CS of L. monocytogenes (LmCS), identification and prioritization of potential lead compounds targeted against LmCS were done. Structure-based virtual screening and docking studies were performed using Autodock tools to retrieve potential candidates with high affinity binding against LmCS model from several ligand repositories. The potency of binding was also checked with other structurally similar CS from Streptococcus pneumoniae (SpCS) and Mycobacterium tuberculosis (MtCS). The sequence and structural studies revealed LmCS was similar to be other CS structures (1Q1L, 1QXO, 1R52, 1R53, 1SQ1, 1UM0, 1UMF, 1ZTB, 2011, 2012, 4ECD and 2G85) with each monomer presenting β-α-β sandwich topology with a central helical core. Molecular docking studies and ADME/Tox results revealed that ZINC03803450 and ZINC20149031 were most potent molecules binding into the active site of LmCS. Other two ligands ZINC13387711 and ZINC16052528 showed a strong binding affinity score against all three structures (LmCS, SpCS and MtCS) and bind to LmCS with the predicted inhibition constant (Ki) values of 22.94 nM and 35.84 nM, respectively. A reported benzofuran-3[2H]-one analog CHEMBL135212 with good ADME/Tox properties and experimental IC50 (nM) value of 7000 nM with SpCS could also be considered as a potential inhibitor of LmCS, as compared to previously reported 41 benzofuran-3[2H]-one analogs against SpCS. This information will assist in discovering those compounds that may act as potent CS inhibitors. Further experimental studies and evaluation of structure-activity relationship could help in the development of potential inhibitors against listeriosis, as well as antibacterial chemotherapy.

A study on dyslipidaemia in subclinical hypothyroidism.

Subclinical hypothyroidism is characterised by elevated serum thyroid stimulating hormone (TSH) concentrations in association with normal free thyroid hormones. The aim of the study was to evaluate the prevalence and pattern of serum lipid alterations in patients with stable subclinical hypothyroidism in comparison to age- as well as sex-matched euthyroid group and also subgroup analysis between them in regard to age of presentation, sex, antithyroperoxidase (anti TPO) positivity, and TSH value. In this study, 100 patients of SCH were recruited, age ranged 17-68 years, majority (78%) being females, presenting mainly with non-specific symptoms and compared with 52 euthyroid control regarding lipid parameters. Of the subclinical hypothyroidism patients, only 10% had goitre and anti TPO was positive in 52% cases. Serum lipoprotein (a) above the age of 20 years, and total cholesterol, triglyceride and low density liporpotein cholesterol in the age group of 40-50 years were significantly elevated. In addition, total cholesterol, triglyceride and low density lipoprotein cholesterol levels in anti TPO positive cases and serum triglyceride and low density lipoprotein cholesterol in anti TPO negative patients showed statistically significant higher levels. In males only lipoprotein (a), but in females total cholesterol, triglyceride, low density lipoprotein cholesterol and liproprotein (a)--all were significantly elevated.