Bhardwaj Snigdha, Nagarajan Kandasamy, Mustafa Elagib Halima, Anwar Sadaf, Zeeshan Najm Mohammad, Bhardwaj Tulika, Kausar Mohd Adnan
KIET School of Pharmacy, KIET Group of Institutions, Ghaziabad, Uttar Pradesh, India.
Geomicrobiology Group, Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
PLoS One. 2025 Apr 22;20(4):e0320841. doi: 10.1371/journal.pone.0320841. eCollection 2025.
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. A complete set of 800 molecules (a novel thiazole derivative library) were docked inside the active region of the LasR receptor before being screened using pharmacokinetic and toxicology studies. Among the derivatives that were examined, compounds D_152, D_153, and L_331 were selected as potential inhibitors of LasR in P. aeruginosa and further studied to obtain a crucial understanding of the binding interactions that take place between inhibitor ligands and LasR. The findings indicated that the pharmacophoric characteristics of the derivative D_152 were comparable to those of the reference thiazole molecule (TC). Moreover, the molecular docking investigations showed that derivative D_152 and reference compound TC both fit the LasR protein's active area well. Furthermore, TC and D_152's amino acid interaction graphs with LasR and CviR are nearly identical. Furthermore, compound D_152's ability to engage with the LasR binding site through the dissolution of the protein's dimer was demonstrated by molecular dynamics modeling tests conducted over a 50 ns time span, demonstrating its function as a LasR antagonist. Additionally, Density Functional Theory (DFT) study was conducted on compound D_152 in order to determine the electron density of a molecule. According to the research findings, the recently produced thiazole derivative (D_152) has the potential to be used as a QSI against the LasR receptor, which would speed up the fight against the pathogenicity of P. aeruginosa that is resistant to multiple drugs.
铜绿假单胞菌是一种极具韧性的病原体，具有多种毒力因子，其表达与群体感应（QS）机制密切相关，群体感应机制促进细胞间相互作用。群体感应（QS）抑制是对抗细菌感染的一种有前景的策略。LasR是一种控制铜绿假单胞菌QS机制的转录因子，是治疗药物开发的一个有前景的靶点，因为已经对其结构进行了大量研究。已经证实噻唑及其化合物对铜绿假单胞菌具有抗QS潜力。本研究旨在利用基于结构的虚拟筛选技术，使用ZINC数据库，从新型噻唑中鉴定新的LasR群体感应抑制剂（QSIs）。在使用药代动力学和毒理学研究进行筛选之前，将完整的800个分子（一个新型噻唑衍生物库）对接至LasR受体的活性区域内。在所研究的衍生物中，化合物D_152、D_153和L_331被选为铜绿假单胞菌LasR的潜在抑制剂，并进一步研究以深入了解抑制剂配体与LasR之间发生的结合相互作用。研究结果表明，衍生物D_152的药效团特征与参考噻唑分子（TC）相当。此外，分子对接研究表明，衍生物D_152和参考化合物TC都能很好地契合LasR蛋白的活性区域。此外，TC和D_152与LasR和CviR的氨基酸相互作用图几乎相同。此外，通过在50纳秒时间跨度内进行的分子动力学建模测试，证明了化合物D_152通过溶解蛋白质二聚体与LasR结合位点结合的能力，证明了其作为LasR拮抗剂的功能。此外，对化合物D_152进行了密度泛函理论（DFT）研究，以确定分子的电子密度。根据研究结果，新产生的噻唑衍生物（D_152）有潜力用作针对LasR受体的QSIs，这将加快对抗耐多药铜绿假单胞菌致病性的斗争。
