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

Igor José Dos Santos Nascimento; Thiago Mendonça de Aquino; Edeildo Ferreira da Silva-Júnior

doi:10.2174/2772270816666220126103909

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

Recent Adv Inflamm Allergy Drug Discov. 2022 Jan 26. doi: 10.2174/2772270816666220126103909. Online ahead of print.

Authors

Igor José Dos Santos Nascimento¹, Thiago Mendonça de Aquino², Edeildo Ferreira da Silva-Júnior²

Affiliations

¹ Estácio of Alagoas College, Pharmacy Department, Maceió, Brazil | Laboratory of Computational Chemistry and Modeling of Biomolecules, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceió-AL, Brazil.
² Laboratory of Computational Chemistry and Modeling of Biomolecules, Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceió-AL, Brazil.

PMID: 35081900
DOI: 10.2174/2772270816666220126103909

Abstract

Background: 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, and to obtain information about the complex stability and main interactions with amino acid residues from NLRP3.

Methods: 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, Rg, SASA, and H-bond plots.

Results: The results of RMSD, RMSF, Rg, 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.

Conclusion: This report confirmed the stability of NP3-146, similar to the know inhibitor MCC950, and provides various information useful to design NLRP3 inhibitors.

Keywords: Anti-inflammatory drugs.; Inflammasomes; Molecular docking; Molecular dynamics; NLRP.