ABSTRACT
Although the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is wreaking havoc and resulting in mortality and morbidity across the planet, novel treatments are urgently needed. Drug repurposing offers an innovative approach in this context. We report here new findings on the in silico potential of several antimalarial drugs for repurposing against COVID-19. We conducted analyses by docking the compounds against two SARS-CoV-2-specific targets: (1) the receptor binding domain spike protein and (2) the main protease of the virus (MPro) using the Schrödinger software. Importantly, the docking analysis revealed that doxycycline (DOX) showed the most effective binding to the spike protein of SARS-CoV-2, whereas halofantrine and mefloquine bound effectively with the main protease among the antimalarial drugs evaluated in the present study. The in silico approach reported here suggested that DOX could potentially be a good candidate for repurposing for COVID-19. In contrast, to decipher the actual potential of DOX and halofantrine against COVID-19, further in vitro and in vivo studies are called for. Drug repurposing warrants consideration as a viable research and innovation avenue as planetary health efforts to fight the COVID-19 continue.
Subject(s)
Antimalarials/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning/methods , Pneumonia, Viral/drug therapy , Antimalarials/chemistry , Antiviral Agents/chemistry , Betacoronavirus/chemistry , Binding Sites , COVID-19 , Computer Simulation , Coronavirus 3C Proteases , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/drug effects , Doxycycline/chemistry , Doxycycline/pharmacology , Drug Evaluation, Preclinical , Humans , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/drug effects , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/drug effects , COVID-19 Drug TreatmentABSTRACT
A focused library of novel benzyl pyrrolones has been synthesized and their in silico molecular docking studies carried out against TNF-α target. Among all the docked molecules, compound 3f showed best glide score of -6.89. All the synthesized compounds were evaluated for in vivo anti-inflammatory activity by carrageenan-induced paw edema model. Compounds showing significant anti-inflammatory activity were further tested for their in vitro TNF α expression. Compounds 3b and 2b were found to show significant inhibition of 76.22% and 71.47%, respectively after 5 h in comparison with standard drug indomethacin, which showed 80.98% inhibition of inflammation. Compounds 3b and 2b also suppressed TNF α level by 65.03% and 60.90% as compared indomethacin, which showed 68.84% of inhibition. Compound 3b showed significant analgesic activity of 60.04%, and its activity was comparable with indomethacin (64.04%). Compounds 3b and 2b were also tested for their effect on protein expression of COX-2 and NF-κB in the liver tissues. Compounds 3b and 2b were further evaluated for their gastric risk and lipid peroxidation action and showed superior GI safety along with reduction of LPO as compared to indomethacin. Hepatotoxicity study showed that these two compounds did not cause any damage to liver.