Antunes Deborah, Santos Lucianna H S, Caffarena Ernesto Raul, Guimarães Ana Carolina Ramos
Laboratory for Applied Genomics and Bioinnovations, Oswaldo Cruz Institute (IOC - FIOCRUZ), Rio de Janeiro, Brazil.
Biomolecular Simulations Group, Institut Pasteur de Montevideo, Montevideo, Uruguay.
J Biomol Struct Dyn. 2025 Jul 30:1-22. doi: 10.1080/07391102.2025.2530092.
Antibiotic resistance poses a significant global health threat, necessitating the development of novel antibacterial strategies. Riboswitches, particularly those sensing purines, have emerged as promising targets for antibiotic development. In an unconventional approach, we explore the repurposing of antiviral compounds as potential antibacterial agents targeting riboswitches. This study employs a comprehensive computational framework to investigate the binding of 2'-deoxyguanosine (2'-dG) and 10 antiviral analogs to the 2'-dG-II riboswitch. We integrated structural similarity analysis, molecular docking, molecular dynamics simulations and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculations to elucidate the molecular basis of ligand recognition and assess the feasibility of antiviral compounds as riboswitch-targeting antibacterials. Our results revealed that the guanine moiety's binding orientation is conserved across all compounds, while interactions involving sugar or sugar-like moieties significantly influence binding stability and specificity. Key nucleotides U22, C51 and C78 play crucial roles in ligand recognition across all complexes. Notably, the antiviral compounds lagociclovir and valganciclovir demonstrated higher binding affinities than the native ligand, with unique interaction patterns. The MM/GBSA analysis provided binding free energies consistent with the experimental data for known compounds, validating our computational approach. This study offers detailed insights into the adaptability of the 2'-dG-II riboswitch binding pocket and identifies promising candidates for riboswitch-targeting antibiotics, contributing to the broader efforts to combat antibiotic resistance through computational drug discovery and repurposing strategies.
抗生素耐药性对全球健康构成重大威胁，因此需要开发新的抗菌策略。核糖开关，特别是那些感应嘌呤的核糖开关，已成为抗生素开发的有希望的靶点。在一种非常规方法中，我们探索将抗病毒化合物重新用作靶向核糖开关的潜在抗菌剂。本研究采用全面的计算框架来研究2'-脱氧鸟苷（2'-dG）和10种抗病毒类似物与2'-dG-II核糖开关的结合。我们整合了结构相似性分析、分子对接、分子动力学模拟和分子力学/广义玻恩表面积（MM/GBSA）自由能计算，以阐明配体识别的分子基础，并评估抗病毒化合物作为靶向核糖开关的抗菌剂的可行性。我们的结果表明，鸟嘌呤部分的结合方向在所有化合物中都是保守的，而涉及糖或类糖部分的相互作用显著影响结合稳定性和特异性。关键核苷酸U22、C51和C78在所有复合物的配体识别中起关键作用。值得注意的是，抗病毒化合物拉科洛韦和缬更昔洛韦表现出比天然配体更高的结合亲和力，具有独特的相互作用模式。MM/GBSA分析提供的结合自由能与已知化合物的实验数据一致，验证了我们的计算方法。本研究详细深入地了解了2'-dG-II核糖开关结合口袋的适应性，并确定了靶向核糖开关的抗生素有希望的候选物，通过计算药物发现和重新利用策略，为抗击抗生素耐药性的更广泛努力做出了贡献。
