A Network Pharmacology Approach to Explore Flavonol Compounds from the KNApSAcK Database as Therapeutic Candidates for COVID-19
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Abstract
COVID-19 is an infectious disease caused by SARS-CoV-2. The identification of new therapeutic candidates targeting multiple proteins and biological pathways may provide an alternative strategy for COVID-19 treatment. This study aimed to investigate the potential of flavonol compounds as multitarget antiviral candidates against COVID-19 using network pharmacology and molecular docking approaches. Flavonol compounds were obtained from the KNApSAcK database and evaluated for drug-likeness based on Lipinski’s Rule of Five using SwissADME. Flavonol-associated protein targets were predicted using SwissTargetPrediction, while COVID-19-related proteins were identified using GeneCards. The overlapping proteins were analyzed using a Venn diagram, followed by protein-protein interaction analysis using STRINGDB to identify potential hub proteins. Of the 25 flavonol compounds evaluated, 21 fulfilled the Lipinski criteria and were retained for further analysis. Network analysis identified 170 overlapping proteins and 16 hub proteins, comprising ACE2, ACE, AGT, REN, TMPRSS2, FURIN, CD4, CD8A, IL6, IL1B, IL10, TNF, IFNG, CRP, CXCL8, and CXCL10. ACE2 showed the highest connectivity and was therefore selected as a representative hub target for molecular docking. Based on docking binding free energy, the four flavonols with the most favorable predicted binding affinities toward ACE2 were Broussonol E, 5,7,3′,4′-tetrahydroxy-6- geranylflavonol, Broussoflavonol A, and Broussoflavonol B, all stronger than baicalein and sharing several interaction residues with the reference compound. These findings support the potential of the investigated flavonols as multitarget antiviral candidates at the network level, involving proteins associated with viral entry, the renin–angiotensin system, and immune and inflammatory responses. However, the present docking analysis provides target-specific structural evidence only for ACE2. Further computational and experimental studies involving the remaining hub proteins are required to validate the proposed multitarget mechanism and antiviral activity.
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