Design of novel hybrid secondary metabolite targets to diguanylate cyclase of Acinetobacter baumannii.

Monalisa Tiwari, Richa Joshi, Vishvanath Tiwari
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引用次数: 4

Abstract

Biofilm formation in bacteria is a resistance determinant and is positively regulated by cyclic diguanylate signaling. This signaling is a near universal signaling, and c-di-GMP produced by diguanylate cyclase (DGC) in this signaling is involved in different bacterial behaviors. The present study aims to find a plant-based novel hybrid therapeutic agent that can target the DGC of Acinetobacter baumannii. In this study, we have tried to design a hybrid molecule from the anti-biofilm plant secondary metabolites and screened its binding with the DGC of A. baumannii. The modeled and validated DGC was used to identify the active site and docking grid. Designed hybrid compounds were analysed for their interaction with the active site residues of DGC of A. baumannii. Further, the binding free energies of the docked complexes obtained from the Generalized Born model and Solvent Accessibility (MMGBSA) were analysed. The results indicated that VR-QEg-180 has a predicted high binding affinity with enzyme DGC as compared to other hybrids, parent secondary metabolites and positive control. Molecular dynamics simulation (MDS) analysis confirmed the interaction of VR-QEg-180 with DGC of the A. baumannii. The designed lead has favorable ADMET properties, has no human off-targets and has no predicted cytotoxicity in cell lines. Therefore, the designed hybrid molecule (VR-QEg-180) targeting the DGC of A. baumannii may play a very significant role in controlling this pathogen.

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针对鲍曼不动杆菌二胍酸环化酶的新型杂交次级代谢物的设计。
细菌生物膜的形成是一个抗性决定因素,并受到环二胍信号的积极调节。该信号是一种接近通用的信号,二胍酸环化酶(DGC)在该信号中产生的c-二gmp参与了不同的细菌行为。本研究旨在寻找一种以植物为基础的靶向鲍曼不动杆菌DGC的新型杂交治疗剂。在本研究中,我们试图从抗生物膜植物次生代谢物中设计一个杂交分子,并筛选其与鲍曼不动杆菌DGC的结合。将模型和验证的DGC用于识别活性位点和对接网格。对设计的杂化化合物与鲍曼不动杆菌DGC活性位点残基的相互作用进行了分析。进一步分析了由广义Born模型得到的对接物的结合自由能和溶剂可及性(MMGBSA)。结果表明,与其他杂交种、亲本次生代谢物和阳性对照相比,VR-QEg-180与DGC酶具有较高的结合亲和力。分子动力学模拟(MDS)分析证实了VR-QEg-180与鲍曼不动杆菌DGC的相互作用。设计的铅具有良好的ADMET特性,没有人体脱靶,并且在细胞系中没有预测的细胞毒性。因此,设计的靶向鲍曼不动杆菌DGC的杂交分子(VR-QEg-180)可能在防治鲍曼不动杆菌中发挥重要作用。
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来源期刊
CiteScore
3.30
自引率
0.00%
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0
审稿时长
15 weeks
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