In silico study directed towards identification of the key structural features of GyrB inhibitors targeting MTB DNA gyrase: HQSAR, CoMSIA and molecular dynamics simulations

Abstract

In silico Study Directed Towards Identification the Key Structural Feature of GyrB Inhibitors Targeting MTB DNA Gyrase: HQSAR, CoMSIA and Molecular Dynamics Simulations MTB DNA gyrase subunit B (GyrB) has been identified as 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 CoMISA and 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 urea core of inhibitors has strongest interaction with Asp79 via hydrogen bond interactions. In addition, cation-pi interaction and hydrophobic interactions of R2 subsituent with Arg82 and Arg141 help to enhance the binding affinity in GyrB ATPase binding site. Thus, the present study beneficially provides crucial structural feature and a structural concept for rational design of novel DNA gyrase inhibitors with improved biological activities against both enzyme and mycobacterial cell; good pharmacokinetic properties and drug safely profiles.

Revealing the Interaction Mechanism between Mycobacterium tuberculosis GyrB and Novobiocin, SPR719 through Binding Thermodynamics and Dissociation Kinetics Analysis

“…Specifically, Asp79 is highlighted for its ability to form hydrogen bonds with inhibitors. This aligns with the results of Kamsri et al's [35] MD simulation study on GyrB inhibitors of thiadiazole derivatives, which also identified Asn52, Asp79, Arg82, Ile84, and Arg141 as key residues contributing significantly to energy residue and emphasizing their critical role in inhibitor binding. The study conducted by Gl et al [36] identified some novel drug candidates targeting GyrB through drug repurposing.…”

Computer-aided identification of Mycobacterium tuberculosis resuscitation-promoting factor B (RpfB) inhibitors from Gymnema sylvestre natural products

“…Benz(e)-azulene-3,8-dione and the reference compound benzamidine showed no cytochrome inhibitory potential. These enzymes are responsible for 90% of drug metabolism as well as interfering with the metabolism of a variety of endogenous substances ( Kamsri et al, 2019 ). This suggests that these compounds would not have restrictions due to the inhibition of these cytochromes and would not be metabolized in the body.…”

“…The SMILES codes of the top compounds were generated and used as input files. The results were presented as scores ranging from 0 to 1, where the value 1 corresponds to the most likely target of the query molecule ( Kamsri et al, 2019 ).…”

Advancement of GyrB Inhibitors for Treatment of Infections Caused by Mycobacterium tuberculosis and Non-tuberculous Mycobacteria

“…The structure of coumermycin A1 bound to E. coli and Thermus thermophilus GyrB was recently published and provides a path to improved analogues of that natural product class using SBDD . A recent report of quantitative structure–activity relationship (QSAR) studies coupled with molecular dynamics (MD) provided insights into the key structural features and binding interactions of potent mycobacterial GyrB inhibitors . Importantly, this analysis identified structural features that result in both ATPase inhibitory activity and antimycobacterial activity (mycobacterial cell wall permeability).…”

“…42 A recent report of quantitative structure− activity relationship (QSAR) studies coupled with molecular dynamics (MD) provided insights into the key structural features and binding interactions of potent mycobacterial GyrB inhibitors. 43 Importantly, this analysis identified structural features that result in both ATPase inhibitory activity and antimycobacterial activity (mycobacterial cell wall permeability). Novel benzothiazole ureas were proposed based on this evaluation that are predicted to be potent GyrB inhibitors with improved antimycobacterial activity.…”