A multi-targeted approach to identify potential flavonoids against three targets in the SARS-CoV-2 life cycle.

The advent and persistence of the Severe Acute Respiratory Syndrome Coronavirus - 2 (SARS-CoV-2)-induced Coronavirus Disease (COVID-19) pandemic since December 2019 has created the largest public health emergency in over a century. Despite the administration of multiple vaccines across the globe, there continues to be a lack of approved efficacious non-prophylactic interventions for the disease. Flavonoids are a class of phytochemicals with historically established antiviral, anti-inflammatory and antioxidative properties that are effective against cancers, type 2 diabetes mellitus, and even other human coronaviruses. To identify the most promising bioactive flavonoids against the SARS-CoV-2, this article screened a virtual library of 46 bioactive flavonoids against three promising targets in the SARS-CoV-2 life cycle: human TMPRSS2 protein, 3CLpro, and PLpro. By examining the effects of glycosylation and other structural-activity relationships, the presence of sugar moiety in flavonoids significantly reduces its binding energy. It increases the solubility of flavonoids leading to reduced toxicity and higher bioavailability. Through protein-ligand contact profiling, it was concluded that naringin formed more hydrogen bonds with TMPRSS2 and 3CLpro. In contrast, hesperidin formed a more significant number of hydrogen bonds with PLpro. These observations were complimented by the 100 ns molecular dynamics simulation and binding free energy analysis, which showed a considerable stability of docked bioflavonoids in the active site of SARS-CoV-2 target proteins. Finally, the binding affinity and stability of the selected docked complexes were compared with the reference ligands (camostat for TMPRSS2, GC376 for 3CLpro, and GRL0617 for PLpro) that strongly inhibit their respective SARS-COV-2 targets. Overall analysis revealed that the selected flavonoids could be potential therapeutic agents against SARS-CoV-2. Naringin showed better affinity and stability for TMPRSS2 and 3CLpro, whereas hesperidin showed a better binding relationship and stability for PLpro.

Selection of animal models for COVID-19 research.

The researcher community across the globe is on a search for a promising animal model that closely mimics the clinical manifestation of SARS-CoV-2. Though some developments were seen such as serial adaptation in various animal species or the creation of genetically engineered models, a suitable animal model remains elusive. A model that could display the severity of human illness and can be used for the fast-track evaluation of potential drugs as well as for the clinical trials of vaccines is an urgent need of the hour. In the light of huge information generated on SARS-CoV-2 and daily updates received from the research community, we have chosen to review the current status of animal models of SARS-CoV-2 in encompassing the areas of viral replication, transmission, active/passive immunization, clinical disease, and pathology. The review is intended to help the researchers in the selection of appropriate animal models for SARS CoV-2 research in the fight against the current global pandemic.