Purpose: 2019 Coronavirus disease (COVID-19) has caused millions of confirmed cases and deaths worldwide. TMPRSS2-mediated hydrolysis and maturation of spike protein is essential for SARS-CoV-2 infection . The latest research found that a TMPRSS2 inhibitor called N-0385 could effectively prevent the infection of the SARS-CoV-2 and its variants. However, it is not clear about the mechanism of N-0385 treatment COVID-19. Therefore, this study used computer simulations to investigate the mechanism of N-0385 treatment COVID-19 by impeding SARS-CoV-2 infection.

Methods: The GeneCards database was used to search disease gene targets, core targets were analyzed by PPI, GO and KEGG. Molecular docking and molecular dynamics were used to validate and analyze the binding stability of small molecule N-0385 to target proteins. The supercomputer platform was used to simulate and analyze the number of hydrogen bonds, binding free energy, stability of protein targets at the residue level, radius of gyration and solvent accessible surface area.

Results: There were 4,600 COVID-19 gene targets from GeneCards database. PPI, GO and KEGG analysis indicated that signaling pathways of immune response and inflammation played crucial roles in COVID-19. Molecular docking showed that N-0385 could block SARS-CoV-2 infection and treat COVID-19 by acting on ACE2, TMPRSS2 and NLRP3. Molecular dynamics was used to demonstrate that the small molecule N-0385 could form very stable bindings with TMPRSS2 and TLR7.

Conclusion: The mechanism of N-0385 treatment COVID-19 was investigated by molecular docking and molecular dynamics simulation. We speculated that N-0385 may not only inhibit SARS-CoV-2 invasion directly by acting on TMPRSS2, ACE2 and DPP4, but also inhibit the immune recognition process and inflammatory response by regulating TLR7, NLRP3 and IL-10 to prevent SARS-CoV-2 invasion. Therefore, these results suggested that N-0385 may act through multiple targets to reduce SARS-CoV-2 infection and damage caused by inflammatory responses.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9622768PMC
http://dx.doi.org/10.3389/fmicb.2022.1013911DOI Listing

Publication Analysis

Top Keywords

mechanism n-0385
16
molecular docking
16
molecular dynamics
16
docking molecular
12
sars-cov-2 infection
12
n-0385 treatment
12
treatment covid-19
12
n-0385
9
sars-cov-2
8
covid-19
8

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!