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

• Published in: Computers in biology and medicine Vol. 142; p. 105231
• Main Authors: Kumar, Sanjay, Paul, Pradipta, Yadav, Pardeep, Kaul, Ridhima, Maitra, S.S., Jha, Saurabh Kumar, Chaari, Ali
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.03.2022; Elsevier Limited; The Author(s). Published by Elsevier Ltd
• Subjects: 3CLpro; Affinity; Amino acids; Aniline Compounds; Animals; Antiviral activity; Antiviral drugs; Benzamides; Binding energy; Bioavailability; Biocompatibility; Bioflavonoids; Biological activity; Chemical compounds; Computational studies; Coronaviruses; COVID-19; COVID-19 drug discovery; COVID-19 vaccines; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2; Enzymes; Epidemics; Flavonoids; Flavonoids - pharmacology; Free energy; Genomes; Glycosylated flavonoids; Glycosylation; Hesperidin; Humans; Hydrogen bonding; Hydrogen bonds; In silico; Inflammation; Life Cycle Stages; Life cycles; Ligands; Medical research; Middle East respiratory syndrome; Molecular Docking Simulation; Molecular dynamics; Naphthalenes; Naringin; Natural products; Pandemics; Pharmacology; PLpro; Polypeptides; Proteins; Public health; Respiratory diseases; RNA polymerase; SARS-CoV-2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Stability analysis; TMPRSS2; Toxicity; Vaccines; Ventilation; Viral diseases; Virtual libraries; COVID-19; Glycosylated flavonoids; SARS-CoV-2; Naringin; Natural products; Computational studies; In silico; TMPRSS2; 3CLpro; PLpro; Hesperidin; COVID-19 drug discovery
• ISSN: 0010-4825; 1879-0534
• DOI: 10.1016/j.compbiomed.2022.105231

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. [Display omitted] •Structure based virtual screening was used to screen 46 bioflavonoids against SARS-CoV-2 target proteins.•Two bioflavonoids i.e., hesperidin and naringin, with highest negative docking score (−7.5 to −10 kcal/mol) were selected.•Glycosylated bioflavonoids were showing lesser binding energy and toxicity along with increased solubility and bioavailability.•Molecular dynamics simulation and MM-GBSA calculation revealed naringin as potential inhibitor of TMPRSS2 and 3CLpro whereas hesperidin inhibiting PLpro.