Flavonoids are naturally occurring compounds found in fruits and vegetables that exhibit a variety of beneficial physiological activities [1]. Quercetin has three important medicinal properties: anti-inflammatory, antioxidant, and immunomodulatory. Due to combination of these three properties, quercetin is an excellent candidate for dealing with situations involving oxidative stress, inflammation, and the immune system [1]. The lower oral bioavailability of quercetin limits its clinical use [2]. In silico study of selected flavonoids aids in the identification of potential drug candidates. The purpose of this study is to investigate the anti-covid activity of some selected flavonoids using molecular docking analysis and assess the efficiency of quercetin in Covid-19 infection prevention.

Important pharmacological effects of quercetin include its antiviral, pro-metabolic, and anti-inflammatory properties. Moreover, a variety of anticancer qualities have been shown for it, and numerous publications support its effectiveness as a cancer preventative. The substance has a wide range of therapeutic benefits, including effects on the immune system, cardioprotection, and neuroprotection, as well as antioxidant and anti-inflammatory characteristics. The antioxidant and free radical scavenging properties of quercetin are primarily responsible for its neuroprotective benefits [3]. Flavonoids with strong binding to SARS-CoV-2 targets include apigenin and quercetin. Orally, isoquercetin is bioavailable. Isoquercetin functions as an antioxidant by scavenging free radicals and preventing oxidative cell damage [4].

Angiotensin-converting enzyme ACE2 is a membrane-associated protein found in a variety of cell types, including lung alveolar epithelial cells and vascular endothelial cells. SARS-coronaviruses, including the 2019-nCoV new coronavirus, enter the body through ACE2 [5].

It is possible to prevent this virus from entering cells if these receptors are not present.

Quercetin and Isoquercetin have often been at the top of the list of potential effectors in silico screening of small molecules for binding affinity to proteins involved in the SARS-CoV-2 life cycle. Clinical trials may be conducted to examine the preventative and therapeutic effects of these flavonoids for COVID-19 if these predictions hold true and in vitro tests confirm them [6, 7].

The best method for evaluating ligands against prospective therapeutic targets is in silico studies. In addition, lower binding energy is significant.

Table 2 displays the findings of the docking investigation. The ligands under study have binding energies and inhibition factors that range from -6.74 kcal/mol to -3.4 kcal/mol and 11.51 uM to 3.23 mM, respectively. Therefore, isoquercetin displayed the lowest binding energy and inhibition coefficient among the substances examined. The compounds' comparable binding sites demonstrate that functional groups were responsible for the binding properties.

The energy decomposition results for the selected 11 compounds in Table 3 revealed that the residues Met165, Pro168, Glu 166, Gln189, and Gln 192 play important roles in compound binding. Polar and hydrophobic interactions dominated interactions with these residues (Table 3). Quercetin demonstrated good binding affinity in a study by Zang et al. [12] that screened 115 compounds found in Chinese medicinal plants. Manjesh et al. [13] conducted a docking study in which they docked various coronavirus proteins with quercetin ligands and found binding energies ranging from -3.37kcal/mol to -6.71kcal/mol. Keretsu et al. used a variety of modeling experiments to identify protease inhibitors from a database of prospective 3CLpro inhibitors [14].

An open-label randomised controlled clinical trial conducted at King Edward Medical University's Department of Medicine under clinical trial id NCT04861298 suggests a therapeutic role for quercetin in early-stage COVID-19, including SARS-CoV-2 clearance, early resolution of acute symptoms, and modulation of the host's hyperinflammatory response [15]. Quercetin has the potential to treat severe inflammation and life-threatening conditions in COVID-19 patients [16]. According to the current study, isoquercetin has a higher binding affinity to the receptor than quercetin. Animal studies on oral bioavailability show that isoquercetin has higher oral bioavailability than quercetin [17].

In vitro studies of flavonoid compounds showed inhibitory activity against SARS CoV 2 M^pro IC₅₀ values ranging from 0.125 to 12.9µM. Studies on the Inhibitory effects of quercetin and isoquercitrin on the replication of HCoV-229E in Huh-7 cells showed that Isoquercetin strongly inhibited the replication starting with 2.5 μM [18]. Quercetin is one of the most common flavonoid compounds having five hydroxyl groups with electron-donating activity at positions 3, 5, 7, 3’, and 4’ [19]. In addition, to the above isoquercetin bears a single glucose moiety while losing an OH group. This alteration not only increases its hydrophilicity and water solubility by four times compared to quercetin’s. After oral administration, isoquercetin produces a maximum plasma concentration of quercetin that is 1.7 to 10 times greater when pharmacokinetic characteristics are compared [20].

ACE2 is essential to the pathogenesis of SARS-CoV-2 because it acts as a receptor and a conduit for virus particles to enter, causing the recently discovered outbreak [21]. Due to its inhibitory effect on the expression of the human ACE2 receptors, SARSCoV-2 enzymes (MPro, PLPro, and RdRp), antioxidant activity, anti-inflammatory activity, and immunomodulatory activity, quercetin has the potential to be used as a preventative or therapeutic agent against COVID-19, as shown by clinical trials, inventive compositions, and patent literature [22].

Out of the 11 compounds we studied, all exhibited a good, expected affinity for the major protease of SARS-CoV-2, a top target in the COVID-19 drug discovery. Among the compounds screened, Isoquercetin displayed binding energy scores of -6.7 kcal/mol, which indicates a robust interaction with the protease target. Isoquercetin is a better drug than quercetin because it has lower binding energy for docking studies and higher oral bioavailability. The study recommends Isoquercetin as a potential molecule candidate for an anti-COVID-19 role. It strongly supports the execution of a case-control clinical study to realize its possible efficacy within the context of this disease.