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 (IC<sub>50</sub> 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.
Authors
- Sondos Musleh (ORCID: https://orcid.org/0000-0002-2272-4566)
- Sherihan El‐Sayed (ORCID: https://orcid.org/0000-0001-6325-6546)
- Sally Freeman (ORCID: https://orcid.org/0000-0002-3831-9151)
- Paul R. Kasher (ORCID: https://orcid.org/0000-0002-9213-502X)
- Richard A. Bryce (ORCID: https://orcid.org/0000-0002-8145-2345)
- David Brough (ORCID: https://orcid.org/0000-0002-2250-2381)
- Emily McMahon
Institutions
- Zagazig University (EG)
- Manchester Academic Health Science Centre (GB)
- University of Manchester (GB)
Publication Details
- Journal
- Bioorganic Chemistry
- Published
- 2024-10-22
- DOI
- https://doi.org/10.1016/j.bioorg.2024.107909
- Citations
- 3
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- UK Research and Innovation
- Ministry of Higher Education, Egypt
- Jordan University of Science and Technology
- Medical Research Council