Page 101 - congress

ORAL PRESENTATION / SÖZLÜ SUNUM

Discovery of Novel NLRP3 Inhibitors via the Virtual Screening Approach

Fehmi Metehan BENLI * Agnieszka K. BRONOWSKA
1,
2

1 Ondokuz Mayıs University, Faculty of Veterinary Medicine, Department of Veterinary
Pharmacology and Toxicology, Samsun, TÜRKIYE
2 Newcastle University, Faculty of Science, Agriculture & Engineering, Department of
Chemistry, Newcastle upon Tyne, UK

*Correspound Author: fehmimetehan.benli@omu.edu.tr

NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome plays a

pivotal role in the innate immune system by regulating caspase-1 activation, the secretion of

IL-1β/IL-18, and gasdermin D-mediated pyroptotic cell death. Dysregulated activation of
NLRP3 has been implicated in the pathogenesis of chronic inflammatory, cardiovascular,

and neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. The most
potent inhibitor reported, MCC950, was discontinued in phase II clinical trials due to

hepatotoxicity. Here, we applied a structure-based drug discovery workflow combining large-
scale virtual screening and molecular dynamics simulations to identify novel NLRP3

inhibitors. The prioritized compounds represent unique chemotypes, devoid of indacene,
sulfonylurea, and carboxylic acid scaffolds, and are structurally distinct from previously

reported NLRP3 inhibitors. The inhibitory activity of the selected compounds was tested in
primary bone marrow–derived macrophages using a standard NLRP3 inflammasome

activation assay. Several compounds exhibited significant inhibition of IL-1β release at low

micromolar concentrations, whereas a subset showed moderate or partial inhibitory effects.
This study, based on both in silico and in vitro approaches, identified multiple promising lead

candidates with unique chemical novelty, which may offer new opportunities for
inflammasome inhibition.

Keywords: NLRP3 inflammasome, In Silico, Structure-Based Drug Discovery, Molecular
Docking, Molecular Dynamic Simulation.

Acknowledgement: I would like to extend my sincere appreciation to my sponsor, the
Republic of Türkiye Ministry of National Education, for providing me with the scholarship that

has made my academic journey possible.

98