Discussion
The global spread of SARS-CoV-2 requires urgent and novel therapeutic discoveries given the high failure rate of traditional drug discovery methods (Mirabelli et al. 2021). Attentions have been constantly drawn to natural compounds due to their relatively lower side effects (Lin et al. 2017). In light of this, different anthocyanins have been previously shown to be good inhibitors of SARS-CoV-2 molecular targets (Fakhar et al. 2021; Messaoudi et al. 2021).
Eight anthocyanins with impressive binding data were identified from 118 anthocyanins screened, and they were found to show robust binding affinity to the protein targets. Hydrogen bonding is the major form of interaction observed in the binding data. In all categories, the identified anthocyanins have higher binding affinity than the standard drugs: remdesivir and hydroxychloroquine. C1, C2, C3, C5, and C8 showed impressive binding affinity to SARS-CoV-2 3CL protease. The protein functions in the maturation of viral polyprotein and is essential for the completion of SARS-CoV-2 life cycle (Kan et al. 2005). Therefore, inhibiting this protein is a proven therapeutic option in curbing coronavirus disease. All the compounds exhibited good binding affinity to 3CL protease but C1, C2, C3, C5, and C5 have greater binding than the other compounds. Similarly, C1, C2, C3, C4, and C8 showed excellent binding affinity to SARS-CoV-2 helicase. The helicase protein, also called non-structural protein 13 (NSP 13), has been identified as a target for antivirals due to its role in viral replication (Newman et al. 2021). Of all compounds tested, C4 had the highest docking score (− 11.72) and the pharmacophore model showed that hydrogen bond and aromatic rings contribute substantially to its binding to NSP13.
All the test compounds (Fig. 1) exhibited good molecular binding affinity to RNA-dependent RNA polymerase (RdRp) also named NSP 12. The docking scores of the compound ranged from − 12.73 to − 8.91 with C3 having the highest binding affinity to the protein. C3 interacted with seven amino acids in the active site of NSP12 (THR319, SER255, ASP390, THR393, THR394, SER397, and ASN459).
Only C2 (− 10.07) showed a good binding affinity to the receptor-binding domain of the viral spike protein required for viral entry into the host’s cell. Finally, all the compounds exhibited robust binding affinity (− 11.42 to − 13.9) to the fifth protein target: human angiotensin-converting enzyme 2 (ACE2) which is the receptor for SARS-CoV-2 entry into the human host.
Considering the heat map of the docking scores (Fig. 3), it can be adjudged that C2 is the most suitable multitarget antiviral agent against SARS-CoV-2 among the compounds reported. Similarly, C1, C3, and C8 also showed promising inhibitory potential against the target proteins.
ADMET profile
The predicted value of log P measures the lipophilicity of the compounds. For better accuracy, the arithmetic mean of five different models of the partition coefficient of n-octanol to water was adopted as the log P in this study. An oral drug candidate must be sufficiently lipophilic to enable it to cross the intestine into the systemic circulation. C7 had the highest (0.42) log P value and is predicted to be the most lipophilic of all compounds tested. The value of Silicos-IT Log SW as predicted by SwissADME represents the degree of solubility in water. C2 was found to be the most water-soluble. Drugs are transported to the cells that need them through the hydrophilic systemic circulation; therefore, a drug candidate must be sufficiently hydrophilic to aid its transport in the systemic circulation.
The pharmacokinetic screening of the compounds showed that they all have a bioavailability sore of 0.17. Abbot Bioavailability Score is the likelihood of a compound having greater than 10% bioavailability in rats or measurable Caco-2 permeability (Martin 2005).
All the compounds are predicted to be non-substrates of the CYP isoforms engaged and would not elicit a drug–drug interaction. Cytochrome P450 is a family of highly similar enzymes that play a big role in the metabolism and excretion of various compounds. Studies have suggested that about 50–90% of biologically active compounds are substrates of five isoforms of the superfamily (CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4) (Diana et al. 2017), and inhibition of the activity of these enzymes can cause a drug–drug response (Huang et al. 2008).