Abstract
NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) activation has been linked to several chronic pathologies, including atherosclerosis, type-II diabetes, fibrosis, rheumatoid arthritis, and Alzheimer’s disease. Therefore, NLRP3 represents an appealing target for the development of innovative therapeutic approaches. A few companies are currently working on the discovery of selective modulators of NLRP3 inflammasome. Unfortunately, limited structural data are available for this target. To date, MCC950 represents one of the most promising noncovalent NLRP3 inhibitors. Recently, a possible region for the binding of MCC950 to the NLRP3 protein was described but no details were disclosed regarding the key interactions. In this communication, we present an in silico multiple approach as an insight useful for the design of novel NLRP3 inhibitors. In detail, combining different computational techniques, we propose consensus-retrieved protein residues that seem to be essential for the binding process and for the stabilization of the protein–ligand complex.
Highlights
NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) inflammasome is a cytosolic complex that coordinates innate immunity responses by sensing a wide range of damage- and pathogen-associated molecular patterns (DAMPs and PAMPs)
Increased activation of NLRP3 has been related to several chronic pathologies, including neurodegenerative diseases, atherosclerosis, type-II diabetes, fibrosis, and rheumatoid arthritis
We suggest that the most promising key interactions could be Phe257, Val267, Thr268, Gln269, Ser271, Leu272, Asp274, Leu275, Pro281, Pro283, Asn284, Ile287, Lys289, Ile330, Leu331, and Leu332 residues, which seem to be of importance for the binding of MCC950 and derivatives, within the NLRP3 NACHT domain
Summary
NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) inflammasome is a cytosolic complex that coordinates innate immunity responses by sensing a wide range of damage- and pathogen-associated molecular patterns (DAMPs and PAMPs). Many research groups have been focusing on the development of selective modulators of the NLRP3 inflammasome, without interfering with the protective activity of other types of inflammasome. The lack of structural information regarding the oligo-protein and the unclear molecular mechanism of known inhibitors hinders the task of designing novel NLRP3 modulators. Recent studies [3,4,5] showed that MCC950 inhibits NLRP3 in a noncovalent way, and seems to bind in the region proximal to the Walker B motif (296–315), within the NACHT domain, affecting the protein activity. A homology model of the protein was developed and used in a computational workflow to unveil putative protein hot spots involved in the stabilization of the protein–ligand complex with well-known inhibitors (used as a probe), in order to better understand their molecular mechanism
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