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