Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria, Universidad de Buenos Aires, Buenos Aires, Argentina.
CONICET-Universidad de Buenos Aires, Unidad de Microanálisis y Métodos Físicos en Química Orgánica (UMYMFOR), Buenos Aires, Argentina.
J Biomol Struct Dyn. 2022 Jul;40(10):4488-4495. doi: 10.1080/07391102.2020.1860828. Epub 2020 Dec 28.
The outbreak of COVID-19, the disease caused by SARS-CoV-2, continues to affect millions of people around the world. The absence of a globally distributed effective treatment makes the exploration of new mechanisms of action a key step to address this situation. Stabilization of non-native Protein-Protein Interactions (PPIs) of the nucleocapsid protein of MERS-CoV has been reported as a valid strategy to inhibit viral replication. In this study, the applicability of this unexplored mechanism of action against SARS-CoV-2 is analyzed. During our research, we were able to find three inducible interfaces of SARS-CoV-2 N protein NTD, compare them to the previously reported MERS-CoV stabilized dimers, and identify those residues that are responsible for their formation. A drug discovery protocol implemented consisting of docking, molecular dynamics and MM-GBSA enabled us to find several compounds that might be able to exploit this mechanism of action. In addition, a common catechin skeleton was found among many of these molecules, which might be useful for further drug design. We consider that our findings could motivate future research in the fields of drug discovery and design towards the exploitation of this previously unexplored mechanism of action against COVID-19.Communicated by Ramaswamy H. Sarma.
SARS-CoV-2 引起的 COVID-19 疫情继续在全球范围内影响数百万人。由于缺乏全球分布的有效治疗方法，探索新的作用机制是解决这一问题的关键步骤。稳定中东呼吸综合征冠状病毒（MERS-CoV）核衣壳蛋白的非天然蛋白-蛋白相互作用（PPIs）已被证明是抑制病毒复制的有效策略。在这项研究中，分析了针对 SARS-CoV-2 的这种未探索作用机制的适用性。在研究过程中，我们能够找到 SARS-CoV-2 N 蛋白 NTD 的三个诱导界面，将它们与之前报道的稳定化的 MERS-CoV 二聚体进行比较，并确定负责它们形成的残基。我们实施了一个药物发现方案，包括对接、分子动力学和 MM-GBSA，使我们能够找到几种可能利用这种作用机制的化合物。此外，在许多这些分子中发现了一个常见的儿茶素骨架，这可能对进一步的药物设计有用。我们认为，我们的研究结果可能会激发药物发现和设计领域的未来研究，以利用针对 COVID-19 的这种以前未探索的作用机制。由 Ramaswamy H. Sarma 传达。
