College of Chemistry, Pingyuan Laboratory, Zhengzhou University, Zhengzhou, China.
College of Pharmacy, Zhengzhou University, Zhengzhou, China.
J Mol Recognit. 2024 Nov;37(6):e3101. doi: 10.1002/jmr.3101. Epub 2024 Sep 2.
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 IC 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 × 10 Lmol), the quenching constant (5.41 × 10 Lmol), 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.
新型冠状病毒 2 主蛋白酶（Mpro）是一种促进病毒转录和复制的必需酶。Mpro 在不同变体中的保守性质及其与人类蛋白酶的非重叠性质使其成为治疗新型冠状病毒的有吸引力的靶点。在这项工作中，通过分子对接、酶抑制试验、紫外可见光谱、荧光光谱和圆二色性光谱研究了 Mpro 与二吲哚甲烷衍生物之间的相互作用机制。IC 值结果表明，1p（9.87 μM）是本工作中对 Mpro 抑制作用最强的抑制剂，可显著抑制 Mpro 的活性。结合常数（4.07×10 Lmol）、猝灭常数（5.41×10 Lmol）和热力学参数表明，1p 的猝灭方式为静态猝灭，1p 与 Mpro 之间的主要作用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成为 Mpro 的抑制剂。这项工作证实了 1p 引起的 Mpro 微环境的变化，并为潜在抑制剂的设计提供了线索。
