Molecular simulation-based investigation of thiazole derivatives as potential LasR inhibitors of Pseudomonas aeruginosa
Snigdha Bhardwaj, Kandasamy Nagarajan, Halima Mustafa Elagib, Sadaf Anwa, Mohammad Zeeshan Najm, Tulika Bhardwaj, Mohd Adnan Kausar
Abstract
Pseudomonas aeruginosa (P. aeruginosa), a very resilient pathogen, demonstrates a diverse array of virulence factors, the expression of which is closely linked to the quorum sensing(QS) mechanism, which facilitates cell-cell interaction. Quorum sensing (QS) inhibition is a promising strategy for combating bacterial infections. LasR, a transcriptional factor that controls the mechanism of QS in P. aeruginosa, is a promising target for therapeutic development, because a lot of research has been done on its structure. It has already been established that thiazoles and their compounds have anti-QS potential against P aeruginosa. The study aims to identify new LasR quorum sensing inhibitors (QSIs) derived from novel thiazoles utilizing a structure-based virtual screening technique using the ZINC database.
Introduction
Gram-negative, rod-shaped P. aeruginosa is an opportunistic, multidrug-resistant bacteria that can cause serious infections in humans. The bacteria is known for its inherent and sophisticated antimicrobial resistance mechanisms, which lead to severe hospital-acquired infections, particularly those with weakened immune systems and pneumonia related with ventilator use [1,2]. P. aeruginosa demonstrates a varied range of virulence factors, the expression of which is contingent upon the quorum sensing (QS) system, encompassing intercellular communication. The QS mechanism in P. aeruginosa is of significant importance in the dissemination of infections.
Materials and method
2.1. Docking
2.1.1. Data set preparation.
A reference molecule used was a thiazole compound (TC), specifically 2-((2-Chloroquinolin-3-yl)methylene)hydrazono)-3-methyl-2,3dihydrobenzo[d]thiaz, which has been confirmed to be a QSI for LasR of P. aeruginosa. The reference compounds’ two-dimensional chemical structure was delineated and optimized geometrically using Chem Bio Draw ultra-version 12.0 2010, developed by Cambridge Soft, specifically Chem Bio office Ultra in 2010. The conformation of a molecule was stabilized through the utilization of the Molecular Mechanics 2 (MM2) force field, which facilitated geometric optimization and energy minimization. Once the energy minimization process was completed, all files were saved in mol2 format [39]. The chemical is present. In order to prepare the ligands, the mol2 format was loaded into AutoDock Vina v. 1.1.2. Fig 1 displays the reference molecule.
Results and discussion
Chromobacterium violaceum (C. violaceum), namely the CviR/LuxR homologue, has been extensively employed as a prototype bacteria in the first evaluation of QSI for various gram-negative microorganisms, such as P. aeruginosa [65–67]. C. violaceum generates violacein, a QS-controlled purple pigment, and serves as a useful model for understanding the method of action of many traditional medicines. The QS system of this biomonitor strain is made up of the LuxI/LuxR homologue CviI/CviR. N-hexanoyl-L-acyl homoserine lactone (C6-AHL) and N-decanoyl-L-homoserine lactone (C10-HSL), which are autoinducer molecules made by autoinducer synthase CviI, are used by the CviI/CviR system to boost the expression of violacein synthesis, these molecules attach to the CviR (receptor protein). Molecular modeling was utilized because it can accurately predict the activity and binding affinities of possible QSI drugs against the protein active sites of test pathogens, P. aeruginosa and C. violaceum [68].
Conclusion
The reference molecule (TC), which is a recognized QSI of P. aeruginosa, was subjected to molecular docking simulations utilizing the intuitive interface of the molecular docking application AutoDock Vina. For the LasR and CviR receptors, molecular coupling simulations based on crystal structure were performed. The docking simulations conducted with Pymol software to generate the molecular complexes of LasR-OHN were superimposed onto the co-crystallized structure of LasR. The hydrophobic and hydrogen bonding interactions of these complexes with amino acid residues were identical to those of the native ligand (OHN) in its co-crystallized state. Similar to the native ligand (HLC) in its co-crystallized state, the molecular docking simulation utilizing the co-crystallized structure of CviR (PDB ID: 3QP5) uncovered hydrophobic and hydrogen bond interactions with the amino acid.
Citation: Bhardwaj S, Nagarajan K, Mustafa Elagib H, Anwar S, Zeeshan Najm M, Bhardwaj T, et al. (2025) Molecular simulation-based investigation of thiazole derivatives as potential LasR inhibitors of Pseudomonas aeruginosa.
PLoS ONE 20(4): e0320841. https:/
Editor: Tung Truong-Thanh, Phenikaa University, VIET NAM
Received: July 30, 2024; Accepted: February 25, 2025; Published: April 22, 2025
Copyright: © 2025 Bhardwaj et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper.
Funding: This research has been funded by Deputy for Research & Innovation, Ministry of Education through Initiative of Institutional Funding at University of Ha’il – Saudi Arabia through project number IFP-22 103. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
