虚拟筛选引导的 NLRP3 炎症小体抑制剂支架设计。

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2024-10-22 DOI:10.1016/j.bioorg.2024.107909

Sherihan El-Sayed, Emily McMahon, Sondos Musleh, Sally Freeman, David Brough, Paul R Kasher, Richard A Bryce

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引用次数: 0

摘要

NLRP3 炎症小体是药物发现的一个关键靶点，因为它与一系列炎症相关疾病有关。在这项工作中，我们利用分子相似性、对接和 MD 模拟，通过分层虚拟筛选策略确定了 NLRP3 炎症小体的新抑制剂。在随后的生物学实验中发现的最有效的抑制剂（IC50 为 1 - 4 μM）具有磺酰胺基团（已知的有利于抑制 NLRP3 的基团）和吲哚、苯并呋喃或三环 6,7-二氢-5H-茚并[5,6-b]呋喃环，从而产生了新的支架。这些结构为设计更强效、更具选择性的 NLRP3 抑制剂奠定了基础。

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Virtual screening-led design of inhibitor scaffolds for the NLRP3 inflammasome.

The NLRP3 inflammasome is a key target for drug discovery due to its implication in a range of inflammation-related diseases. In this work, we identify new inhibitors of the NLRP3 inflammasome via a hierarchical virtual screening strategy using molecular similarity, docking and MD simulation. The most potent inhibitors identified from a subsequent biological assay (IC₅₀ of 1 - 4 μM) feature a sulfonamide group, a motif known to favour NLRP3 inhibition, in conjunction with an indole, benzofuran or tricyclic 6,7-dihydro-5H-indeno[5,6-b]furan ring, yielding novel scaffolds. These structures provide a basis for the design of more potent, selective NLRP3 inhibitors.

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.