Molecular Docking and Dynamics Simulation Studies of a Dataset of NLRP3 Inflammasome Inhibitors

The organism's defense against aggressive agents is performed by the innate immune system via activation of pattern-recognition receptors (PRRs). Initially, these agents are recognized by the immune system, resulting in the inflammatory response that activates the pathogen elimination and tissue repair. Inflammasomes are macromolecules related to the host's response to endo or exogenous aggressive agents. Thus, inflammation mediated by inflammasomes plays an important role in the pathogenesis of diseases, such as neurodegenerative disorders, autoimmune diseases, and type 2 diabetes, justifying their attractiveness as drug targets. One of the most important tasks remains in the ATPase nucleotide-binding oligomerization domain nucleotide- binding domain leucine-rich repeat-containing receptors protein 3 (NLRP3), in which the blocking of its oligomerization is related to the functional inhibition of inflammasomes. Here, we performed molecular docking and dynamics simulations for NP3-146, an analog of MCC950, to obtain information about the complex stability and main interactions with amino acid residues from NLRP3.

By using the crystalized structure recently deposited in the protein data bank (7alv), molecular docking in GOLD software and molecular dynamics simulations in GROMACS software were performed to generate the RMSD RMSF, R_g, SASA, and H-bond plots.

The results of RMSD, RMSF, R_g, SASA, and H-bond plots of both complexes confirmed the stability at the active site. Besides, the analyses of the most stable conformation showed that the main interactions are performed with Ala²²⁷, Ala²²⁸, Pro³⁵², Ile⁴¹¹, Phe⁵⁷⁵, and Arg⁵⁷⁸ residues.

This report confirmed the stability of NP3-146, similar to the known inhibitor MCC950, providing useful information for designing NLRP3 inhibitors.