Department of Biotechnology, IIT Roorkee, Uttrakhand-247667, India.
Department of Biology, York University, 4700 Keele Street, Toronto, Canada.
Front Biosci (Landmark Ed). 2020 Mar 1;25(7):1337-1360. doi: 10.2741/4859.
With rising antibiotic resistance at alarming rates in , a major human pathogen, it is important to identify targets for new antimicrobial therapies. A number of two-component systems (TCS) have been implicated in resistance to several antibiotics. The glycopeptide-resistance associated TCS, GraSR, is involved in cationic antimicrobial peptides (CAMPs) resistance through the regulation of , and operons. GraS is a sensor histidine kinase, while GraR is a response regulator transcription factor, which is potential drug target. In lieu of the significance of GraSR in antibiotic resistance and the lack of structural studies on GraR, we undertook to determine the GraR structure through homology modelling. A series of small molecules were virtually screened and the top-scored molecules were analyzed for different pharmacophore properties and assessed for their binding potency to GraR (IC). Further, a molecular dynamics simulation study of GraR-ligand complexes revealed that the predicted molecules exhibited good binding affinities at the dimerization interface of GraR. Thus, these molecules could be suitable inhibitors for the GraR-mediated signalling processes, which may be further utilized to develop novel antimicrobial agents against .
由于 （一种主要的人类病原体）的抗生素耐药性以惊人的速度上升，因此确定新的抗菌治疗靶点非常重要。许多双组分系统（TCS）已被牵连到几种抗生素的耐药性中。糖肽耐药相关 TCS GraSR 通过调节 和 操纵子参与阳离子抗菌肽（CAMPs）的耐药性。GraS 是一种传感器组氨酸激酶，而 GraR 是一种响应调节转录因子，是潜在的药物靶标。鉴于 GraSR 在抗生素耐药性中的重要性以及缺乏对 GraR 的结构研究，我们着手通过同源建模来确定 GraR 的结构。对一系列小分子进行了虚拟筛选，并对得分最高的分子进行了不同药效团特性的分析，并评估了它们与 GraR 的结合效力（IC）。此外，GraR-配体复合物的分子动力学模拟研究表明，预测的分子在 GraR 二聚化界面表现出良好的结合亲和力。因此，这些分子可能是 GraR 介导的信号转导过程的合适抑制剂，可进一步用于开发针对 的新型抗菌剂。
