Development of novel ligands against SARS-CoV-2 M^pro enzyme: an in silico and in vitro Study.

IF 2.8 4区医学 Q3 CHEMISTRY, MEDICINAL Molecular Informatics Pub Date : 2023-11-01 Epub Date: 2023-09-06 DOI:10.1002/minf.202300120

Navid Kaboudi, Nadine Krüger, Maryam Hamzeh-Mivehroud

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Abstract

Background: Despite tremendous efforts made by scientific community during the outbreak of COVID-19 pandemic, this disease still remains as a public health concern. Although different types of vaccines were globally used to reduce the mortality, emergence of new variants of SARS-CoV-2 is a challenging issue in COVID-19 pharmacotherapy. In this context, target therapy of SARS-CoV-2 by small ligands is a promising strategy.

Methods: In this investigation, we applied ligand-based virtual screening for finding novel molecules based on nirmatrelvir structure. Various criteria including drug-likeness, ADME, and toxicity properties were applied for filtering the compounds. The selected candidate molecules were subjected to molecular docking and dynamics simulation for predicting the binding mode and binding free energy, respectively. Then the molecules were experimentally evaluated in terms of antiviral activity against SARS-CoV-2 and toxicity assessment.

Results: The results demonstrated that the identified compounds showed inhibitory activity towards SARS-CoV-2 M^pro .

Conclusion: In summary, the introduced compounds may provide novel scaffold for further structural modification and optimization with improved anti SARS-CoV-2 M^pro activity.

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新型抗SARS-CoV-2 Mpro酶配体的研制:硅化和体外研究

背景:尽管科学界在2019冠状病毒病大流行期间做出了巨大努力，但该疾病仍然是一个公共卫生问题。尽管全球使用了不同类型的疫苗来降低死亡率，但SARS-CoV-2新变种的出现是COVID-19药物治疗中的一个具有挑战性的问题。在这种情况下，小配体靶向治疗SARS-CoV-2是一种很有前途的策略。方法:采用基于配体的虚拟筛选方法，寻找基于nirmatrelvir结构的新分子。各种标准，包括药物相似度，ADME和毒性性能，用于过滤化合物。选择的候选分子分别进行分子对接和动力学模拟，预测结合模式和结合自由能。然后对这些分子进行了抗病毒活性和毒性评价的实验评价。结果:鉴定的化合物对SARS-CoV-2 Mpro具有抑制活性。结论:综上所述，引入的化合物可为进一步的结构修饰和优化提供新的支架，提高抗SARS-CoV-2 Mpro的活性。

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来源期刊

Molecular Informatics CHEMISTRY, MEDICINAL-MATHEMATICAL & COMPUTATIONAL BIOLOGY

CiteScore

7.30

自引率

2.80%

发文量

审稿时长

3 months

期刊介绍： Molecular Informatics is a peer-reviewed, international forum for publication of high-quality, interdisciplinary research on all molecular aspects of bio/cheminformatics and computer-assisted molecular design. Molecular Informatics succeeded QSAR & Combinatorial Science in 2010. Molecular Informatics presents methodological innovations that will lead to a deeper understanding of ligand-receptor interactions, macromolecular complexes, molecular networks, design concepts and processes that demonstrate how ideas and design concepts lead to molecules with a desired structure or function, preferably including experimental validation. The journal''s scope includes but is not limited to the fields of drug discovery and chemical biology, protein and nucleic acid engineering and design, the design of nanomolecular structures, strategies for modeling of macromolecular assemblies, molecular networks and systems, pharmaco- and chemogenomics, computer-assisted screening strategies, as well as novel technologies for the de novo design of biologically active molecules. As a unique feature Molecular Informatics publishes so-called "Methods Corner" review-type articles which feature important technological concepts and advances within the scope of the journal.