The docking modeling was used repeatedly to find the best inhibitors for the HCV NS5B RNA enzyme. The number of hydrogen bonds within the complex's studied ligands is thought to indicate the ligand's stability when it interacts with the HCV NS5B RNA enzyme. Increases in hydrogen bonding are expected to indicate increased docking system stability (Saleh and Elshemey 2017).
The native inhibitor (Sofosbuvir) is utilized as a benchmark against which the binding affinity of other recommended drugs is measured. As illustrated in Fig. 5, the native inhibitor establishes five hydrogen bond interactions with the NS5B RNA enzyme residues (TYR415, ARG200, GLY192, TYR415, and ASN316) and other interactions such as van der Waals, carbon–hydrogen bond, amide π-stacked, Alkyl, π–π T-shaped, and π-alkyl with the TYR448, TYR195, MET414, PHE193, and CYS366 amino acid residues of the target, respectively, by docking modeling. The total energy of the docking system with the native inhibitor is − 30.34 kcal/mol, hydrogen bond energy is − 10.54 kcal/mol, and hydrophobic energy is − 2.954 kcal/mol, according to Table 1. As shown in Fig. 3 and Table 1, the most potent inhibitor (compound 1 in the dataset) forms ten H-bonds interaction with the HCV NS5B enzyme residues (TYR195, TYR448, MET414, TYR415, CYS366, ARG200, and ASN316 and other interactions such as π–π stacked, π-sulfur, and π-alkyl with the PHE193, and CYS366 amino acid residues of the target, respectively, by docking modeling. The total energy of the docking system with compound 1 is − 37.46 kcal/mol, hydrogen bond energy is − 14.56 kcal/mol, and hydrophobic energy is − 2.329 kcal/mol, according to Table 1. This indicates that compound 1 is more potent than the native inhibitor.
After that, several favorable substituents were added to the designated template R location after assessing the docking and molecular properties. This was done automatically in the current study utilizing the Scaffold Grow module in Discovery Studio, followed by docking screening with ICM-pro. When comparing the designed compounds to the template and reference inhibitors, it was discovered that the docking score of the designed compounds (1a–1c) ranges from − 41.71 to − 39.90 kcal/mol, as shown in Table 1, indicating that the designed compounds have lower binding energy and form more stable systems. As a result, these new compounds are novel inhibitors of the HCV NS5B RNA enzyme, and their docking results are compared to compound 1's docking results and Sofosbuvir's docking results as a positive control. The interaction of the suggested compounds was also investigated to provide a clearer interpretation of the outstanding docking scores reported. Tables 1 and 2 show the comprehensive docking data as well as the types of interactions involved. Furthermore, the developed compounds had a binding score of less than − 39.90 kcal/mol, which implies that the novel inhibitors can bind the target efficiently and create a more thermodynamically stable system than the reference inhibitor.
As shown in Fig. 4 and Table 1, the most potent inhibitor (compound 1c) of the designed molecules forms eleven hydrogen bond interactions with the NS5B RNA enzyme residues (TYR195, ARG200, TYR448, ASN316, MET414, TYR415, and CYS366) and other interactions such as carbon–hydrogen bond, π-alkyl, and π-sulfur with the CYS366 amino acid residues of the target, by docking modeling. The total energy of the docking system with the novel inhibitor is − 41.71 kcal/mol, hydrogen bond energy is − 16.52 kcal/mol, and hydrophobic energy is − 2.306 kcal/mol, according to Table 1. In comparison, these values outperform both the template and the reference molecule. A virtual evaluation was performed using Discovery Studio software, which revealed more information about the interactions of molecules 1, 1c, and R with the target receptor (HCV NS5B enzyme with PDB ID: 4WTG). Molecule 1c has a higher degree of favorable interaction with the target receptor than the reference molecule.
The H-bond is the key force driving interactions between the molecule and the target receptor, according to this research, and the interaction energy of the molecules increases as the number of hydrogen bonds increases (Ejeh et al. 2021a; Umar et al. 2020). The number of amino acids participating in the H bond discovered with the proposed compounds was found to be better than Sofosbuvir, as shown in Figs. 4 and 5, respectively, and there are obvious similarities. This may help to provide the chosen compounds with more accurate binding scores for the HCV NS5B enzyme. As a result, as evidenced by the molecular docking data, these new compounds will be effective inhibitors of the HCV NS5B enzyme, demonstrating competitive inhibition with Sofosbuvir. Furthermore, the drug-likeness and pharmacokinetics ADMET features of the proposed compounds were assessed using Sofosbuvir as a reference to ensure that they are feasible drugs.
Because of ADMET risks, many prospective medications never make it to the clinical stage. Due to their importance, ADMET qualities are now being examined in early-stage pharmaceutical research, resulting in a significant reduction in the number of molecules that failed in clinical trials due to poor ADMET properties (Daina et al. 2017; Pires et al. 2018). Computational virtual screening of selected compound (1), designed molecules, and the reference inhibitor was used to assess drug-likeness, including oral bioavailability and synthetic accessibility, utilizing Lipinski's Ro5 (Table 3).
The proposed molecules are regarded to pass Lipinski's requirements because none of them violate more than two and hence can be categorized as drug-like molecules. In addition, an evaluation was carried out using the ABS criterion (Filipovich et al. 2005), with all of the proposed molecules receiving a bioavailability score in the range of 0.55 to 0.11. This standard was based on a probability level of a molecule having an optimal profile of permeability and bioavailability, where 0.55 indicates total obedience of the Lipinski rule of five (Umar et al. 2020), and the rat bioavailability value is 55%, which is a higher probability value than 10%, confirming the designed molecules' drug-likeness.
The synthetic accessibility score is based on a mix of component contributions and a complexity penalty to measure the ease of synthesis of drug-like compounds. The score ranges from 1 (easy processing) to 10 (tough to synthesize) (Ejeh et al. 2021a). Table 3 shows that the proposed inhibitors have synthetic accessibility in the range of 3.99–4.04, indicating that they are easy to synthesize, as opposed to the reference molecule, which has synthetic accessibility of 6.02, indicating that it is difficult to synthesize.
Again, using OSIRIS Property Explorer software, the pharmacological characteristics and drug scores of molecule 1, designed molecules (1a–1c), and Sofosbuvir as reference inhibitors (R) were analyzed, with the results given in Table 4. To compute compound hydrophilicity, the software used the logarithm of the partition coefficient between n-octanol and water (cLogP). A high cLogP score indicates poor absorption; compounds with a cLogP value less than 5.0 are more likely to be well absorbed. All of the designed compounds in the current study have cLogP values of less than 5.0, indicating a high likelihood of being well absorbed. Because a compound's water solubility has a significant impact on its absorption and distribution features, it is a useful metric for evaluating drug transport features. The breakdown of the tablet or capsule is the initial step in the drug absorption process, followed by the dissolution of the effective drug. Low solubility is detrimental to good and efficient oral absorption, and measuring this quality early in the drug development process is critical. The logarithm of the molar concentration (log mol/L) is used to calculate a compound's estimated solubility. Acceptable compounds are those with a log mol/L value between − 4 and 0.5. All the molecules considered have values within this range (Table 4). As a result, the logS values of the designed molecules are appropriate for druggability compounds.
The drug score (ds) integrates drug-likeness, cLogP, logS, molecular weight, and toxicity concerns into one useful score that can be utilized to measure the molecule's total impact to qualify for therapy, which is used to determine the dependability of these proposed entities. The analysis of the proposed molecules in Table 4 reveals that they have ds values in the range of 0.82 to 0.88 (about 82% to 88% of total performances) which are better compared to Sofosbuvir the reference inhibitor with a ds value of 0.31 (31% of total performance). Figures 6 and 7 show side views of the representation of physicochemical characteristics of molecules 1c and reference, respectively, and indicate the performance of those molecules as 1c has a value close to 1 (0.88) as compared to the reference which is not closed to 1 (0.31). Prediction findings from these figures reveal that molecules 1c and Sofosbuvir did not show any toxicity risk alert as displayed in Figs. 6 and 7 in green, respectively, indicating drug-adherent behavior.