Computational Screening of Novel Nitroimidazole Candidates: Targeting Key Enzymes of Oral Anaerobes for Anti-Parasitic Potential.

Touhami Lanez, Maroua Lanez, Riad Lanez, Elhafnaoui Lanez, Badia Talbi-Lanez
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Abstract

Background: The study focuses on evaluating the parasitic potential of novel metronidazole analogs using computational methods. Specifically, it aims to target key enzymes of oral anaerobes, including UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA) of Fusobacterium nucleatum and DNA topoisomerase (Topo) of Prevotella intermedia.

Objective: The objective is to assess the pharmacokinetic and toxicity properties of 368 novel nitroimidazole candidates through virtual screening. Additionally, the study aims to determine the binding affinity of the most promising candidates with the target proteins through molecular docking analyses.

Methods: A combinatorial library of nitroimidazole candidates was constructed, and virtual screening was performed. Molecular docking analyses were conducted to evaluate the binding affinity of selected compounds with MurA and Topo. Further investigation involved molecular dynamic simulation to assess the stability of the compounds within the active sites of MurA and Topo.

Results: All selected compounds exhibited activity against both MurA and Topo. Among them, Mnz11, Mnz12, and Mnz15 demonstrated the lowest binding free energies and IC50 values. Molecular dynamic simulation indicated that these three compounds remained stable within the active sites of MurA and Topo, with RMSD values consistently below 2Å. Additionally, the antibacterial potential of the most potent compound, Mnz15, was evaluated against a series of oral microbes.

Conclusion: The study concludes that the newly identified nitroimidazole candidates show promise as anti-parasitic agents, based on their activity against key enzymes of oral anaerobes and their pharmacokinetic properties evaluated through computational methods.

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新型硝基咪唑候选化合物的计算筛选:针对口腔厌氧菌关键酶的抗寄生虫潜力。
背景:本研究的重点是利用计算方法评估新型甲硝唑类似物的寄生潜力。具体来说,它以口腔厌氧菌的关键酶为目标,包括核酸镰刀菌的 UDP-N- 乙酰葡萄糖胺 1-羧基乙烯基转移酶(MurA)和中间普雷沃菌的 DNA 拓扑异构酶(Topo):目的:通过虚拟筛选评估 368 种新型硝基咪唑候选药物的药代动力学和毒性特性。此外,该研究还旨在通过分子对接分析确定最有希望的候选化合物与靶蛋白的结合亲和力:方法:构建了硝基咪唑候选化合物组合库,并进行了虚拟筛选。进行了分子对接分析,以评估所选化合物与 MurA 和 Topo 的结合亲和力。进一步的研究包括分子动态模拟,以评估化合物在 MurA 和 Topo 活性位点内的稳定性:结果:所有选定的化合物都对 MurA 和 Topo 具有活性。其中,Mnz11、Mnz12 和 Mnz15 的结合自由能和 IC50 值最低。分子动力学模拟表明,这三种化合物在 MurA 和 Topo 的活性位点内保持稳定,RMSD 值始终低于 2 Å。此外,还评估了最强化合物 Mnz15 对一系列口腔微生物的抗菌潜力:研究得出结论:新发现的硝基咪唑候选化合物对口腔厌氧菌的关键酶具有活性,而且通过计算方法评估了它们的药代动力学特性,因此有望成为抗寄生虫药物。
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