Anti-E. coli GYRB Polyclonal antibody

Mycobacterium tuberculosis DNA gyrase subunit B (GyrB) has been identified as a promising target for rational drug design against fluoroquinolone drug-resistant tuberculosis. In this study, we attempted to identify the key structural feature for highly potent GyrB inhibitors through 2D-QSAR using HQSAR, 3D-QSAR using CoMSIA and molecular dynamics (MD) simulations approaches on a series of thiazole urea core derivatives. The best HQSAR and CoMSIA models based on IC50 and MIC displayed the structural basis required for good activity against both GyrB enzyme and mycobacterial cell. MD simulations and binding free energy analysis using MM-GBSA and waterswap calculations revealed that the urea core of inhibitors has the strongest interaction with Asp79 via hydrogen bond interactions. In addition, cation-pi interaction and hydrophobic interactions of the R-2 substituent with Arg82 and Arg141 help to enhance the binding affinity in the GyrB ATPase binding site. Thus, the present study provides crucial structural features and a structural concept for rational design of novel DNA gyrase inhibitors with improved biological activities against both enzyme and mycobacterial cell, and with good pharmacokinetic properties and drug safety profiles.

1-alkyl-2-pyridones, 2a-c, and 2-acyl-2-hydroxypyridines, 3a-b, were synthesized under ultrasonic irradiation. The synthesized compounds were characterized by (HNMR)-H-1 and FTIR spectroscopy. DFT calculations were performed in order to study reactivity of the N and O-sites of 2-hydroxypyridine towards these reactions. The results showed that the electrophilicity index of the alkyl and acyl halide were found to be higher than that of 2-hydroxypyridine. Furthermore, these compounds were screened for antimicrobial activities and were found to be significantly inhibit bacterial and fungal strains. 1-hexyldecyl-2-pyridone (2c) and 2-acyl-2-hydroxypyridines (3a) displayed strong antibacterial activities towards Micrococcus luteus ATCC 10240 and Enterococcus faecalis ATCC 2921. Moreover compound 3a was found to effective inhibit Aspergillus fumigatus ATCC 204305 and Saccharomyces cerevisiae ATCC 9763. Hence to further validate the binding of these compounds, molecular docking studies were performed. The results revealed that compounds 2c and 3a were found to be interactive within the active sites of E. coli DNA gyrase enzyme and cytochrome P450, 14-a-sterol demethylase (CYP51) with good binding affinities. Furthermore, their comparative molecular docking results suggested to the compound 2c have a higher binding affinity than 3a with the selected receptors. (C) 2019 Elsevier B.V. All rights reserved.