Investigating the Inhibition of Diindolylmethane Derivatives on SARS-CoV-2 Main Protease

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Recognition Pub Date : 2024-09-02 DOI:10.1002/jmr.3101

Wenjin Li, Xiaoyu Chang, Hang Zhou, Wenquan Yu, Ruiyong Wang, Junbiao Chang

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引用次数: 0

Abstract

The SARS-CoV-2 main protease (Mpro) is an essential enzyme that promotes viral transcription and replication. Mpro conserved nature in different variants and its nonoverlapping nature with human proteases make it an attractive target for therapeutic intervention against SARS-CoV-2. In this work, the interaction mechanism between Mpro and diindolylmethane derivatives was investigated by molecular docking, enzymatic inhibition assay, UV–vis, fluorescence spectroscopy, and circular dichroism spectroscopy. Results of IC₅₀ values show that 1p (9.87 μM) was the strongest inhibitor for Mpro in this work, which significantly inhibited the activity of Mpro. The binding constant (4.07 × 10⁵ Lmol⁻¹), the quenching constant (5.41 × 10⁵ Lmol⁻¹), and thermodynamic parameters indicated that the quenching mode of 1p was static quenching, and the main driving forces between 1p and Mpro are hydrogen bond and van der Waals force. The influence of molecular structure on the binding is investigated. Chlorine atoms and methoxy groups are favorable for the diindolylmethane derivative inhibitors of Mpro. This work confirms the changes in the microenvironment of Mpro by 1p, and provides clues for the design of potential inhibitors.

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研究二吲哚甲烷衍生物对 SARS-CoV-2 主要蛋白酶的抑制作用

SARS-CoV-2 主要蛋白酶（Mpro）是一种促进病毒转录和复制的重要酶。Mpro 在不同变体中的保守性及其与人类蛋白酶的非重叠性使其成为对 SARS-CoV-2 进行治疗干预的一个有吸引力的靶点。本研究通过分子对接、酶抑制试验、紫外-可见光光谱、荧光光谱和圆二色光谱等方法研究了 Mpro 与二吲哚甲烷衍生物之间的相互作用机制。IC50 值结果表明，1p（9.87 μM）是本研究中对 Mpro 的最强抑制剂，能显著抑制 Mpro 的活性。结合常数（4.07×105 Lmol-1）、淬灭常数（5.41×105 Lmol-1）和热力学参数表明，1p的淬灭方式为静态淬灭，1p与Mpro之间的主要驱动力为氢键和范德华力。研究了分子结构对结合的影响。氯原子和甲氧基有利于二吲哚甲烷衍生物抑制 Mpro。这项工作证实了 1p 对 Mpro 微环境的改变，并为设计潜在的抑制剂提供了线索。

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来源期刊

Journal of Molecular Recognition 生物-生化与分子生物学

CiteScore

4.60

自引率

3.70%

发文量

审稿时长

2.7 months

期刊介绍： Journal of Molecular Recognition (JMR) publishes original research papers and reviews describing substantial advances in our understanding of molecular recognition phenomena in life sciences, covering all aspects from biochemistry, molecular biology, medicine, and biophysics. The research may employ experimental, theoretical and/or computational approaches. The focus of the journal is on recognition phenomena involving biomolecules and their biological / biochemical partners rather than on the recognition of metal ions or inorganic compounds. Molecular recognition involves non-covalent specific interactions between two or more biological molecules, molecular aggregates, cellular modules or organelles, as exemplified by receptor-ligand, antigen-antibody, nucleic acid-protein, sugar-lectin, to mention just a few of the possible interactions. The journal invites manuscripts that aim to achieve a complete description of molecular recognition mechanisms between well-characterized biomolecules in terms of structure, dynamics and biological activity. Such studies may help the future development of new drugs and vaccines, although the experimental testing of new drugs and vaccines falls outside the scope of the journal. Manuscripts that describe the application of standard approaches and techniques to design or model new molecular entities or to describe interactions between biomolecules, but do not provide new insights into molecular recognition processes will not be considered. Similarly, manuscripts involving biomolecules uncharacterized at the sequence level (e.g. calf thymus DNA) will not be considered.