Pharmacophore modeling of bioactive compounds against the respiratory deteriorating virus has been initiated ever since the outbreak of SARS way back at 2002, providing new research ideas for drug discovery projects . Also, extensive investigations on therapeutic targets to SARS-CoV-2 particularly towards spike protein and protease for discovery of potential drugs by screening the library of phytochemical compounds through computational methods have also been reporting linearly since the emergence of this virulent strain lately [3, 30, 31]. The molecular docking is a modeling approach which virtualizes the interaction between ligand and its receptor specifically in atomic level. This tactic magnifies the characteristic properties of a molecule in terms of binding the target thereby one can understand the biochemical process involved. It basically predicts the conformation, position and orientation of a ligand in a binding site with a rate of energy. The thumb rule is that lower the binding energy, higher the affinity towards the target [32, 33]. Notably, the binding energy tested for seselin against multiple targets on SARS-CoV-2 in this study was found to be lower i.e. -6.6 kcal/mol, -6.9 kcal/mol and -6.7 kcal/mol for SARS-CoV-2S spike protein, SARS-CoV-2 main protease (6LU7) and free enzyme of SARS-CoV-2 (2019-nCoV) main protease (6Y2E), respectively, which implies the higher degree of affinity. The binding energies of kamferol, curcumin, pterostilbene, hydroxychloroquine, fisetin, quercetin, isorhamnetin, genistein, luteolin, resveratrol and apigenin reported against the SARS-CoV-2S spike protein are -7.4 kcal/mol, -7.1 kcal/mol, -6.7 kcal/mol, -5.6 kcal/mol, -8.5 kcal/mol, -8.5 kcal/mol, -8.3 kcal/mol, -8.2 kcal/mol, -8.2 kcal/mol, -7.9 kcal/mol and -7.7 kcal/mol and -3.09 kcal/mol, respectively. Similarly, the binding energies of lopinavir, oseltamivir, ritonavir, talampicillin, lurasidone, apigenin, curcumin, glabridi, glycoumarin, glycyrrhizin, hederagenin, liquiritigenin, oleanolic acid, quercetin, rosmarinic acid, safficinolide, sageone, ursolic acid, glucobrassicin, saquinavir, amaranthin and andrographolide reported against the SARS-CoV-2 main protease (6LU7) are -4.1 kcal/mol, -4.65 kcal/mol, -5.11 kcal/mol, -11.17 kcal/mol, -11.17 kcal/mol, -7.8 kcal/mol, -7.0 kcal/mol, -8.0 kcal/mol, -7.5 kcal/mol, -7.2 kcal/mol, -7.6 kcal/mol, -7.7 kcal/mol, -7.8 kcal/mol, -7.3 kcal/mol, -7.1 kcal/mol, -6.8 kcal/mol, -7.1 kcal/mol, -7.6 kcal/mol, -8.1 kcal/mol, -9.2 kcal/mol, -12.67 kcal/mol and -3.09 kcal/mol, respectively. Likewise, the binding energies of apigenin, curcumin, glabridi, glycoumarin, glycyrrhizin, hederagenin, liquiritigenin, oleanolic acid and quercetin reported against the free enzyme of SARS-CoV-2 (2019-nCoV) main protease (6Y2E) are -7.0 kcal/mol, -6.4 kcal/mol, -7.1 kcal/mol, -7.1 kcal/mol, -8.4 kcal/mol, -7.7 kcal/mol, -6.9 kcal/mol, -8.0 kcal/mol and -7.4 kcal/mol, respectively [31, 34-38]. Intermolecular forces including hydrogen bonding determine the binding of a ligand to its receptor. Among various interactions, hydrogen bonding is considered to be crucial for interaction specificity. By participating in receptor-drug complexation, hydrogen bonds play an important role in determining conformational stability and biological activity . Hydrogen bonding can affect membrane transport and the distribution of the drug within the biological system . In the strategy of bioisosterism, hydrogen bond capacity is an important factor for drug design and optimization . On the other hand, amino acid residues are critical for the virus protein to interact with a host receptor and this can create a better application for site-directed mutagenesis to involve in testing the hypothesis for developing an effective antiviral therapies. A docking study on protein complex of SARS-CoV-S1 with ACE2 suggested that proposing a mutated residue would effectively block the receptor binding in turn preventing cellular entry of SARS-CoV . This reported computational study was even strengthened by experimental proof earlier .
Discovery and development of drugs are exorbitant and time-investing. Accurate predictions of the in vivo pharmacokinetics of the drug under study earlier in the process are paramount since this can prevent clinical phase drug development failures. The Lipinski rule assesses five factors that determine the possible and potential interactions between drug and the target. It appraises the tendency of a desired compound to fall under certain essential categories. It states that an orally active drug should comply to a minimum of four of the five laid down criteria that includes (a) molecular mass <500 Dalton (b) high lipophilicity (expressed as LogP<5) (c) less than 5 hydrogen bond donors (d) less than 10 hydrogen bond acceptors (e) molar refractivity between 40-130 . It assures the recognition of absorption of drug, tissue distribution, fate of metabolism, its excretion and toxicity (ADMET) which can optimize the selection of suitable drug candidates for development . Our results on this concern showed that the seselin has potentially cleared all the criteria put forth.
Drug safety assessment is very important which should be evaluated in preclinical and clinical trial phases. Prediction of toxicity of the compound rationalizes possible side-effects and assesses the possibility of repurposing therapeutically-relevant compounds . Cytochrome p450 (CYP) enzymes are important oxidases that help in the metabolism of drugs. Induction or inhibition of the enzyme, CYP3A4 mainly found in the liver and intestine oxidizes small foreign organic molecules such as toxins or drugs may influence the pharmacokinetics of the drug altering their efficacy or toxicity. Another important target of many drugs is hERG (human ether-a-go-go-related protein responsible for Kv11.1, the alpha subunit of a potassium ion channel), the blockage of which can lead to sudden death .
An optimum pharmacokinetic profile is desired because it can prevent unforeseen toxic effects on human . In-depth knowledge of the toxicological profile of the drug molecule is crucial as the toxicity is the reason for the failure of the drug in many clinical trials . One of the most decisive steps in rationalizing a biomolecule is predicting or mapping their targets. This can, in turn, provide molecular insights into the mode of action of the drug candidate, possible side effects or cross-reactivity. For many proteins including kinases and phosphatases, hundreds of ligand molecules are identified. Understanding the probable targets of the bioactive molecule can also help in understanding how a molecule can be chemically modified to improve its bioactivity towards a particular target protein. Probability score calculated can thus provide information on how specific the ligand is to the target that it is directed to . Water solubility (LogS), Caco-2 permeability and topological polar surface area (TPSA) all fell within the reference range. Seselin as an anti-SARS-COV-2 molecule achieved with satisfactory binding affinity and ADMET. The outcome of pharmacokinetic analysis suggests that the compound had favourable drugability properties that further help to eliminate expensive reformulation later.
Along with the antiviral nature of ‘seselin’ in our earlier report as well as other cited reports, it has also been proven to be inhibitor of indole acetic oxidase and peroxidase enzyme , ovicidal , tumor suppressive and anti-HIV , cytotoxic , antinociceptive and vasodilatory , anti-fungal , anti-feedant and larvicidal [55,56] and DNA binding specific , that by showcasing itself in a broad manner of acquiring bioactive potentials. The findings of this study suggest that the in silico multiple target inhibition of seselin on SARS-CoV-2 virus proteins predicted with higher binding affinity, non-toxicity, solubility and stability is proficient and competent for pursuing the experiments to prove in in vitro and in vivo studies to hold its candidacy in therapeutics and drug discovery for COVID-19.