Developing New Dual-Action Antiviral/Anti-Inflammatory Small Molecules For COVID-19 Treatment Using In Silico And In-Vitro Approaches

This study aims to develop new molecular structures as potential therapeutic agents against COVID-19, utilizing both in silico and in vitro studies. Potential targets of cepharanthine (CEP) against COVID-19 to reveal its underlying mechanism of action were evaluated using in silico screening experiments. A library of new molecules was docked into the receptor binding domain of the SARS-CoV-2 spike glycoprotein complex with its receptor, human ACE2, to identify promising compounds. Receptor-oriented docking was performed using the most likely macromolecular targets, aimed at inhibiting key viral replication pathways and reducing inflammatory processes in damaged tissues. The hit molecules showed potential inhibition of Mpro and PLpro proteases of SARS-CoV-2, which are involved in viral replication. They also showed a potential inhibitory effect on Janus kinase (Jak3), which mediates intracellular signaling responsible for inflammatory processes. The in vitro study examined the effects of the selected hit molecules on the generation of superoxide anions and the release of elastase in activated neutrophils, which are factors that exacerbate tissue inflammation and worsen the clinical manifestations of COVID-19. It was demonstrated that 2-((5-((4-isopropylphenyl)sulfonyl)-6-oxo-1,6-dihydropyrimidin-2-yl)thio)-N-(3-methoxyphenyl)acetamide (Hit15) inhibited virus infection by 43.0% at 10 M using pseudovirus assay and suppressed fMLF/CB-induced superoxide anion generation and elastase release in human neutrophils with IC50 values 1.43 and 1.28 M, respectively. Hit15 showed promising activity against coronavirus that can be further developed into a therapeutic agent. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/24316825v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@13607f2org.highwire.dtl.DTLVardef@43a597org.highwire.dtl.DTLVardef@12c7a63org.highwire.dtl.DTLVardef@11711c7_HPS_FORMAT_FIGEXP M_FIG C_FIG