Department of Chemical Technology, University of Calcutta, 92, A.P.C. Road, Kolkata, 700009, India.
Department of Chemical Technology, University of Calcutta, 92, A.P.C. Road, Kolkata, 700009, India.
J Mol Graph Model. 2022 Mar;111:108113. doi: 10.1016/j.jmgm.2021.108113. Epub 2021 Dec 21.
The current ongoing pandemic of COVID-19 urges immediate treatment measures for controlling the highly contagious SARS-CoV-2 infections. The papain-like protease (PLpro), which is released from nsp3, is presently being evaluated as a significant anti-viral drug target for COVID-19 therapy development. Particularly, PLpro is implicated in the cleavage of viral polyproteins and antagonizes the host innate immune response through its deubiquitinating and deISGylating actions, thus making it a high-profile antiviral therapeutic target. The present study reports a few specific food compounds that can bind tightly with the SARS-CoV-2 PLpro protein identified through extensive computational screening techniques. Precisely, extensive advanced computational approaches combining target-based virtual screening, particularly employing sub-structure based similarity search, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA based binding free energy calculations have been employed for the identification of the most promising food compounds with substantial functional implications as SARS-CoV-2 PLpro protein inhibitors/modulators. Observations from the present research investigation also provide a deeper understanding of the binding modes of the proposed four food compounds with SARS-CoV-2 PLpro protein. In docking analyses, all compounds have established essential inter-molecular interaction profiles at the active site cavity of the SARS-CoV-2 PLpro protein. Similarly, the long-range 100 ns conventional MD simulation studies also provided an in-depth understanding of probable interactions and dynamic behaviour of the SARS-CoV-2 PLpro protein-food compound complexes. Binding free energies of all molecular systems revealed a strong interaction affinity of food compounds towards the SARS-CoV-2 PLpro protein. Moreover, clear-cut comparative analyses against the known standard inhibitor also suggest that proposed food compounds may act as potential active chemical entities for modulating the action of the SARS-CoV-2 PLpro protein.
当前 COVID-19 的大流行迫切需要采取治疗措施来控制高传染性的 SARS-CoV-2 感染。目前，从 nsp3 释放的木瓜蛋白酶样蛋白酶（PLpro）被评估为 COVID-19 治疗开发的重要抗病毒药物靶标。特别是，PLpro 参与病毒多蛋白的切割，并通过去泛素化和去 ISGylating 作用拮抗宿主先天免疫反应，因此成为一个备受关注的抗病毒治疗靶标。本研究通过广泛的计算筛选技术，报告了一些可以与 SARS-CoV-2 PLpro 蛋白紧密结合的特定食物化合物。具体来说，采用了广泛的先进计算方法，包括基于靶标的虚拟筛选，特别是基于子结构的相似性搜索、分子对接、分子动力学（MD）模拟和基于 MM-GBSA 的结合自由能计算，用于鉴定具有重要功能意义的最有前途的食物化合物作为 SARS-CoV-2 PLpro 蛋白抑制剂/调节剂。本研究还提供了对所提出的四种食物化合物与 SARS-CoV-2 PLpro 蛋白结合模式的更深入理解。在对接分析中，所有化合物在 SARS-CoV-2 PLpro 蛋白的活性位点腔中都建立了重要的分子间相互作用模式。同样，长达 100 ns 的常规 MD 模拟研究也深入了解了 SARS-CoV-2 PLpro 蛋白-食物化合物复合物的可能相互作用和动态行为。所有分子系统的结合自由能揭示了食物化合物对 SARS-CoV-2 PLpro 蛋白的强烈相互作用亲和力。此外，与已知标准抑制剂的明确比较分析表明，所提出的食物化合物可能作为调节 SARS-CoV-2 PLpro 蛋白作用的潜在有效化学实体。
