Abstract
Designing anticoronavirus disease 2019 (anti-COVID-19) agents is the primary concern of medicinal chemists/drug designers nowadays. Repurposing of known active compounds against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new effective and time-saving trend in anti-COVID-19 drug discovery. Thorough inhibition of the coronaviral-2 proteins (i.e., multitarget inhibition) is a possible powerful favorable strategy for developing effectively potent drugs for COVID-19. In this new research study, I succeeded to repurpose the two antioxidant polyhydroxy-1,3,4-oxadiazole compounds CoViTris2020 and ChloViD2020 as the first multitarget coronaviral protein blockers with extremely higher potencies (reach about 65 and 304 times, for CoViTris2020, and 20 and 93 times, for ChloViD2020, more potent than remdesivir and favipiravir, respectively). These two 2,5-disubstituted-1,3,4-oxadiazoles were computationally studied (through molecular docking in almost all SARS-CoV-2 proteins) and biologically assessed (through a newly established robust in vitro anti-COVID-19 assay) for their anticoronaviral-2 bioactivities. The data obtained from the docking investigation showed that both ligands promisingly exhibited very strong inhibitory binding affinities with almost all docked enzymes (e.g., they displayed extremely lower binding energies of – 12.00 and – 9.60 kcal/mol, respectively, with the SARS-CoV-2 RNA-dependent RNA polymerase “RdRp”). The results of the biological assay revealed that CoViTris2020 and ChloViD2020 significantly displayed very high anti-COVID-19 activities (anti-SARS-CoV-2 EC 50 = 0.31 and 1.01 μM, respectively). Further in vivo/clinical studies for the development of CoViTris2020 and ChloViD2020 as anti-COVID-19 medications are required. In brief, the ascent of CoViTris2020 and ChloViD2020 as the two lead members of the novel family of anti-COVID-19 polyphenolic 2,5-disubstituted-1,3,4-oxadiazole derivatives represents a promising hope in COVID-19 therapy. CoViTris2020 and ChloViD2020 inhibit SARS-CoV-2 life cycle with surprising EC 50 values of 0.31 and 1.01 μM, respectively. CoViTris2020 strongly inhibits coronaviral-2 RdRp with exceptionally lower inhibitory binding energy of – 12.00 kcal/mol.
Keywords: Anti-COVID-19 drug; ChloViD2020; CoViTris2020; Coronaviral-2; Coronavirus; Favipiravir; Ivermectin; Papain-like protease (PLpro); Polyphenolic 2,5-disubstituted-1,3,4-oxadiazole; RNA-dependent RNA polymerase (RdRp); Remdesivir; SARS-CoV-2.
【저자키워드】 Ivermectin, SARS-CoV-2, coronavirus, Remdesivir, Favipiravir, Anti-COVID-19 drug, ChloViD2020, CoViTris2020, Coronaviral-2, Papain-like protease (PLpro), Polyphenolic 2,5-disubstituted-1,3,4-oxadiazole, RNA-dependent RNA polymerase (RdRp), 【초록키워드】 COVID-19, Ivermectin, SARS-CoV-2, coronavirus, therapy, Drug discovery, molecular docking, Remdesivir, Favipiravir, repurposing, drug, docking, protease, in vitro, severe acute respiratory syndrome Coronavirus, anti-SARS-CoV-2, antioxidant, binding affinity, binding energy, activity, Papain-like protease, Protein, Research, Clinical studies, RdRP, RNA-dependent RNA polymerase, COVID-19 therapy, RNA polymerase, respiratory, medication, PLPro, disease, Ligand, SARS-CoV-2 proteins, biological assay, lead, life cycle, binding affinities, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, SARS-CoV-2 life cycle, enzyme, Compound, Papain, lower binding energy, blocker, Coronaviral, oxadiazole, derivative, inhibitory, effective, robust, significantly, inhibit, required, exhibited, docked, inhibit SARS-CoV-2, the SARS-CoV-2, 【제목키워드】 COVID-19, therapy,