Activity modeling of newly designed EGFRWT inhibitors
The predictive power of the model developed in our previous study (Eq. 1) was further confirmed in this study by modeling/predicting the pIC50 of these newly designed EGFRWT inhibitors (Table 2). The model was not just chosen but because of its significance with R2trng = 0.9459, R2adj = 0.9311, Q2cv = 0.8947, R2test = 0.7008, and LOF = 0.1195 . From the table, it can be inferred that the predicted pIC50 of these newly designed EGFRWT inhibitors (range from 7.746966 to 11.09261) were better than that of the hit compound with pIC50 of 7.563837 and gefitinib the positive control used in this study with pIC50 of 5.879426. This further reaffirmed the high predicting performance of the model used in modeling the pIC50 of these newly designed EGFRWT inhibitors.
Molecular docking of newly designed EGFRWT inhibitors
The ligand-binding interaction between these newly designed EGFRWT inhibitors and the EGFR tyrosine kinase receptor as shown in Table 3 was investigated and elucidated using the molecular docking protocol. Based on the molecular docking results, the binding affinities of these newly designed EGFRWT inhibitors were found to be between − 8.8 and − 9.5 kcal/mol. The designed compound SFD10 has the highest binding affinity of − 9.5 kcal/mol followed by compound SFD8 (with a binding affinity of − 9.3 kcal/mol), then by compound SFD9 and 4 (each with a binding affinity of − 9.3 kcal/mol).
SFD10 (− 9.5 kcal/mol) formed conventional and carbon-hydrogen bonds with THR790 (2.48 Å) and PRO794 (3.31 Å) amino acids backbone of the receptor. Besides hydrogen bonds, it formed halogen with ALA743, ILE744, and LEU788 amino acids, electrostatics bond with LYS745 amino acid, and hydrophobic bond with LYS745, LEU792, LYS728, PRO794, VAL726, and LEU718 amino acid residues of the receptor.
The second best designed compound SFD8 (− 9.3 kcal/mol) formed a conventional hydrogen bond with PRO794 (2.61178 Å) and LYS745 (2.23017 Å) amino acid residues. It also formed a carbon-hydrogen bond with PHE795 (3.35205 Å) and TYR801 (3.6175 Å). On the other hand, it also formed a halogen bond with LYS745 amino acids. In addition to the halogen bond, it formed a hydrophobic bond with PHE795, GLY796, LEU844 (2), LEU718, VAL726, ALA743 (2), LYS745, and HIS805 amino acid residues of the target protein.
Only one conventional carbon-hydrogen bond interaction was observed between the designed compound SFD9 (− 9.2 kcal/mol) and the binding site of the target protein with PRO794 (2.43) amino acid residue. Also, two carbon-hydrogen bond interactions were observed between the designed compound SFD9 and the binding site of the target protein with GLN791 (3.52) and PHE795 (3.42) amino acid residues, respectively. The following amino acid residues PHE795, GLY796, ALA743, MET793, LEU788, LEU718, LEU844, VAL726, and LYS745 were also observed between the designed compound SFD9 and the binding site of the target protein employing hydrophobic interaction.
SFD4 among the designed compounds with higher affinity (− 9.2 kcal/mol) toward the target interacted in the binding site of the target receptor with PRO794 (2.46) and THR790 (2.32) residues employing conventional carbon-hydrogen bond. Two carbon-hydrogen bond interactions were observed between the designed compound SFD4 and the binding site of the target protein with GLN791 (3.33) and MET793 (3.79) amino acid residues, respectively. The binding site of the receptor was seen to interact with SFD4 employing hydrophobic interaction with PHE795, GLY796, MET793, LEU844, MET766, LEU718, LEU844, and VAL726. Not only that, ALA743 and LEU788 amino acid residues were observed to interact with SFD4 employing a halogen bond. LYS745 amino acid in the binding site of the receptor interacted with SFD4 employing electrostatic interaction.
The following amino acid residues, PRO794, LEU718, ALA743, VAL726, and LYS745 are common to the best designed compounds which might be the reason why they have a higher binding affinity. On comparing the designed compounds with the template and the control gefitinib, the designed compounds possessed better binding energy than the template and the control gefitinib. Furthermore, the 3D and 2D structures of the best four discussed designed compounds are shown in Figs. 2, 3, 4 and 5.
Pharmacokinetic properties of newly designed EGFRWT inhibitors
The drug-likeness properties of the designed compounds were also predicted following Lipinski’s rule of five (Table 4). All the newly designed compounds were found to have one violation for Lipinski’s rule of five (WM > 500). The number of hydrogen bond donors and acceptors for all was less than 5 and 10, respectively. The TPSA and the WLOGP values were less than 140 Å and 5, respectively. The synthetic accessibility scores of these newly designed compounds on the scale were in the easy portion (< 5). It means that there is high tendency these newly designed compounds can be easily synthesize in the laboratory. On that basis, the newly designed compounds predicted to be drug-like compounds, orally bioavailable, and active [21, 22].
The predicted ADMET properties of these newly designed compounds are represented in Table 5. The intestinal absorption values for these newly designed compounds were all above 90% but less than 100. Their intestinal absorption values have passed the threshold value of 30%, which clearly shows that these newly designed compounds have high human intestinal absorption properties. The BBB permeability (log BB) values of all newly designed series F compounds were all < − 1, which implies that all these newly designed compounds are poorly distributed through the brain. The CNS permeability (Log PS) values for all were > − 2 which are considered to penetrate the central nervous system. Moreover, they were found to be both substrate and inhibitors of CYP3A4, thereby affirming their metabolic properties. Furthermore, the total clearance for a drug molecule in the body for these newly designed compounds was within the accepted value. All the newly designed compounds were found to be non-toxic. Based on these predicted parameters, the newly designed compounds are said to have high absorption value, low toxicity level, and good permeability across the cell membrane. In general, all these newly designed NSCLC drugs were predicted to have good pharmacokinetic profiles [21, 22].