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计算对接作为指导吴茱萸碱衍生物作为潜在 SARS-CoV-2 抑制剂的药物设计的工具。

Computational Docking as a Tool in Guiding the Drug Design of Rutaecarpine Derivatives as Potential SARS-CoV-2 Inhibitors.

机构信息

Center for Chinese Medicine, Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.

State Key Laboratory of Molecular Neuroscience, Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.

出版信息

Molecules. 2024 Jun 3;29(11):2636. doi: 10.3390/molecules29112636.

DOI:10.3390/molecules29112636
PMID:38893512
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11173897/
Abstract

COVID-19 continues to spread around the world. This is mainly because new variants of the SARS-CoV-2 virus emerge due to genomic mutations, evade the immune system and result in the effectiveness of current therapeutics being reduced. We previously established a series of detection platforms, comprising computational docking analysis, S-protein-based ELISA, pseudovirus entry, and 3CL protease activity assays, which allow us to screen a large library of phytochemicals from natural products and to determine their potential in blocking the entry of SARS-CoV-2. In this new screen, rutaecarpine (an alkaloid from ) was identified as exhibiting anti-SARS-CoV-2 activity. Therefore, we conducted multiple rounds of structure-activity-relationship (SAR) studies around this phytochemical and generated several rutaecarpine analogs that were subjected to in vitro evaluations. Among these derivatives, RU-75 and RU-184 displayed remarkable inhibitory activity when tested in the 3CL protease assay, S-protein-based ELISA, and pseudovirus entry assay (for both wild-type and omicron variants), and they attenuated the inflammatory response induced by SARS-CoV-2. Interestingly, RU-75 and RU-184 both appeared to be more potent than rutaecarpine itself, and this suggests that they might be considered as lead candidates for future pharmacological elaboration.

摘要

COVID-19 继续在全球范围内传播。这主要是因为 SARS-CoV-2 病毒的新变种由于基因组突变而出现，逃避了免疫系统，导致当前治疗方法的有效性降低。我们之前建立了一系列检测平台，包括计算对接分析、基于 S 蛋白的 ELISA、假病毒进入和 3CL 蛋白酶活性测定，这些平台使我们能够筛选来自天然产物的大量植物化学物质库，并确定它们在阻止 SARS-CoV-2 进入方面的潜力。在这个新的筛选中，吴茱萸碱（一种来自 的生物碱）被鉴定为具有抗 SARS-CoV-2 活性。因此，我们围绕这种植物化学物质进行了多轮结构-活性关系（SAR）研究，并生成了几种吴茱萸碱类似物，对其进行了体外评估。在这些衍生物中，RU-75 和 RU-184 在 3CL 蛋白酶测定、基于 S 蛋白的 ELISA 和假病毒进入测定（野生型和奥密克戎变异株）中均表现出显著的抑制活性，并且它们减轻了由 SARS-CoV-2 诱导的炎症反应。有趣的是，RU-75 和 RU-184 似乎都比吴茱萸碱本身更有效，这表明它们可能被视为未来药理学研究的潜在候选药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/08328330eca9/molecules-29-02636-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/85ec06c5d485/molecules-29-02636-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/49db6a71b48d/molecules-29-02636-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/823cd9948be4/molecules-29-02636-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/e23a96afd9b6/molecules-29-02636-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/993f4d056ffa/molecules-29-02636-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/caffb2c3240d/molecules-29-02636-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/44dcfe88d9ad/molecules-29-02636-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/66ef617a9e0b/molecules-29-02636-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/08328330eca9/molecules-29-02636-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/85ec06c5d485/molecules-29-02636-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/49db6a71b48d/molecules-29-02636-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/823cd9948be4/molecules-29-02636-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/e23a96afd9b6/molecules-29-02636-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/993f4d056ffa/molecules-29-02636-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/caffb2c3240d/molecules-29-02636-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/44dcfe88d9ad/molecules-29-02636-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/66ef617a9e0b/molecules-29-02636-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c2b/11173897/08328330eca9/molecules-29-02636-g009.jpg

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