2. Academic Validation
  3. Virtual screening-led design of inhibitor scaffolds for the NLRP3 inflammasome

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

  • Bioorg Chem. 2024 Oct 22:153:107909. doi: 10.1016/j.bioorg.2024.107909.
Sherihan El-Sayed 1,  Emily McMahon 2,  Sondos Musleh 3,  Sally Freeman 4,  David Brough 2,  Paul R Kasher 2,  Richard A Bryce 5
Affiliations

Affiliations

  • 1 Division of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Oxford Road, M13 9PT, UK; Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
  • 2 Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK; Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and the University of Manchester, Manchester M6 8HD, UK.
  • 3 Division of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Oxford Road, M13 9PT, UK; Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan.
  • 4 Division of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Oxford Road, M13 9PT, UK.
  • 5 Division of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Oxford Road, M13 9PT, UK. Electronic address: richard.bryce@manchester.ac.uk.
PMID: 39467507 DOI: 10.1016/j.bioorg.2024.107909
Abstract

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.

Keywords

Docking; ELISA; Inflammasome; MD simulation; NLRP3; Virtual screening.

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