In Silico Insights towards the Identification of NLRP3 Druggable Hot Spots

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.

Inhibiting the NLRP3 Inflammasome

“…A homology model of NLRP3 was prepared from the crystal structure of NLRC4 and the FASTA sequence of human NLRP3 ( ). Perricone and coworkers used this homology model in a Molecular Dynamics (MD) study with MCC950 ( Figure 5 ) and its analogues [ 51 ]. Detection of all potential druggable binding sites close to the Walker B region were detected by docking MCC950 as a probe, using grid-based and geometry-based algorithm approaches.…”

Quinones as preventive agents in Alzheimer’s diseases: focus on NLRP3 inflammasomes

“…In this study, the most promising NLRP3 specific inhibitor MCC950 was selected as the control, [ 101 ] was a potential therapeutic for NLRP3‐associated diseases. [ 102 ] Docking study has shown that MCC950 binding with amino acid residues, such as Arg165, Thr167 and Thr379.…”

Targeting SARS‐CoV‐2 RBD Interface: a Supervised Computational Data‐Driven Approach to Identify Potential Modulators

“…It is noteworthy that this bi‐molecular interaction is not a traditional example of PPI, in which the interaction interfaces are often shallow with lack of deep pockets and it does not bear a canonical active site to target with a synthetic ligand. In general, in PPI, both protein partners establish high affinity contacts through the so‐called hot spot amino acids . These residues are mainly hydrophobic and usually widely dislocated along the whole protein surfaces, and thus sequentially not connected among them within the same protein, creating a discontinuous epitope .…”

“…In general, in PPI, both protein partners establish high affinity contacts through the so-called hot spot amino acids. [62] These residues are mainly hydrophobic and usually widely dislocated along the whole protein surfaces, and thus sequentially not connected among them within the same protein, creating a discontinuous epitope. [63][64][65] Notably, from the currently available PDB structures of ACE2-S protein interaction (PDB IDs: 6M17 and 6M0J), the complex shows a one to one interaction pattern, where the contacts between the two proteins are mediated mainly by hydrogen bonds, some salt bridges and few Van der Waals forces.…”