Background. Aliarcobacter butzleri is a Gram-negative, curved or spiral-shaped, microaerophilic bacterium and causes human infections, specifically diarrhea, fever, and sepsis. The research objective of this study was to employ computer-aided drug design techniques to identify potential natural product inhibitors of a vital enzyme in this bacterium. The pyrimidine biosynthesis pathway in its core genome fraction is crucial for its survival and presents a potential target for novel therapeutics. Hence, novel small molecule inhibitors were identified (from traditional Chinese medicinal (TCM) compound library) against it, which may be used for possible curbing of infection by A. butzleri. Methods. A comprehensive subtractive genomics approach was utilized to identify a key enzyme (orotidine--phosphate decarboxylase) cluster conserved in the core genome fraction of A. butzleri. It was selected for inhibitor screening due to its vital role in pyrimidine biosynthesis. TCM library ( compounds) was screened against it using pharmacophore model based on orotidylic acid (control), and the obtained lead-like molecules were subjected to structural docking using AutoDock Vina. The top-scoring compounds, ZINC70454134, ZINC85632684, and ZINC85632721, underwent further scrutiny via a combination of physiological-based pharmacokinetics, toxicity assessment, and atomic-scale dynamics simulations (100 ns). Results. Among the screened compounds, ZINC70454134 displayed the most favorable characteristics in terms of binding, stability, absorption, and safety parameters. Overall, traditional Chinese medicine (TCM) compounds exhibited high bioavailability, but in diseased states (cirrhosis, renal impairment, and steatosis), there was a significant decrease in absorption, Cmax, and AUC of the compounds compared to the healthy state. Furthermore, MD simulation demonstrated that the ODCase-ZINC70454134 complex had a superior overall binding affinity, supported by PCA proportion of variance and eigenvalue rank analysis. These favorable characteristics underscore its potential as a promising drug candidate. Conclusion. The computer-aided drug design approach employed for this study helped expedite the discovery of antibacterial compounds against A. butzleri, offering a cost-effective and efficient approach to address infection by it. It is recommended that ZINC70454134 should be considered for further experimental analysis due to its indication as a potential therapeutic agent for combating A. butzleri infections. This study provides valuable insights into the molecular basis of biophysical inhibition of A. butzleri through TCM compounds.

中文翻译：

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探索中药类铅分子治疗巴特氏菌的方法：计算机毒性评估、动力学模拟和药代动力学分析

背景。巴特氏菌是一种革兰氏阴性、弯曲或螺旋形、微需氧细菌，会引起人类感染，特别是腹泻、发烧和败血症。本研究的研究目的是采用计算机辅助药物设计技术来识别该细菌中重要酶的潜在天然产物抑制剂。其核心基因组部分中的嘧啶生物合成途径对其生存至关重要，并为新疗法提供了潜在靶点。因此，（从传统中药（TCM）化合物库中）鉴定出针对它的新型小分子抑制剂，可用于抑制A. butzleri的感染。方法。利用综合消减基因组学方法鉴定了A. butzleri核心基因组部分中保守的关键酶（乳清苷-磷酸脱羧酶）簇。由于其在嘧啶生物合成中的重要作用，因此被选择用于抑制剂筛选。中医图书馆（使用基于乳清酸（对照）的药效团模型对其进行筛选，并使用 AutoDock Vina 对获得的先导分子进行结构对接。通过结合基于生理学的药代动力学、毒性评估和原子级动力学模拟（100 ns），对得分最高的化合物 ZINC70454134、ZINC85632684 和 ZINC85632721 进行了进一步审查。结果。在筛选的化合物中，ZINC70454134 在结合、稳定性、吸收和安全参数方面表现出最有利的特性。总体而言，中药化合物表现出较高的生物利用度，但在疾病状态（肝硬化、肾功能损害和脂肪变性）下，与健康状态相比，化合物的吸收、Cmax和AUC显着降低。此外，MD 模拟表明 ODCase-ZINC70454134 复合物具有优异的总体结合亲和力，并得到 PCA 方差比例和特征值等级分析的支持。这些有利的特性强调了其作为有前途的候选药物的潜力。结论。本研究采用的计算机辅助药物设计方法有助于加快针对A. butzleri 的抗菌化合物的发现，为解决 A. butzleri 感染提供了一种经济有效的方法。建议考虑对 ZINC70454134 进行进一步的实验分析，因为它是对抗A. butzleri感染的潜在治疗剂。这项研究为通过中药化合物生物物理抑制A. butzleri的分子基础提供了有价值的见解。