The treatment of epidermal growth factor receptor (EGFR)-muted non-small cell lung cancer (NSCLC) remains among the utmost important unachieved therapeutic need worldwide. Development of EGFR inhibitors to treat NSCLC mutations has been among the difficult tasks faced by researchers in this area. As such, there is a need to discover more EGFR inhibitors. The purpose of this work is to perform computer-aided/structure-based design of novel EGFR inhibitors, elucidate their nature of interactions with their target, and also assess their ADMET properties as well as their drug-likeness, respectively. Compound 17 with a highest binding affinity of −9.5kcal/mol was identified as the template hit compound using molecular docking virtual screening in our previous work. The compound interacted with the active site of the EGFR receptor via hydrogen bond with the following amino acid residues MET793, MET793, THR854, and ASP855 with bond distances of 2.61394 (Å), 2.18464 (Å), 2.57601 (Å), and 2.68794 (Å), respectively. It also interacted with the active site of the EGFR receptor via halogen bond (GLN791), hydrophobic bond (LEU718, CYS797, LYS745, ALA743, ALA743, and VAL726), electrostatic bond (LYS745), and others (MET766), respectively. Furthermore, from our previous study, the following descriptors (ATSC6m, ATSC8e, MATS7m, SpMax3_Bhp, SpMax5_Bhs, and MaxHBint10) contained in the reported model were found to be responsible for the inhibitory activities of the studied compounds. In this research, the template (compound 17) was modified manually by attaching halo-phenyl and halo-phenyl-amino rings on the para position of the flouro-nitro-benzamide moiety of the template compound, respectively.
A computer-aided design/structure-based approach was used to design six new EGFR inhibitors using molecule 17 as the template compound for the design identified in our previously reported work. Molecular docking investigation was performed to elucidate the binding mode of these newly designed EGFR inhibitors with the binding pose of EGFR receptor (pdb code 4ZAU) and found to have better affinities which range from −9.5 to −10.4 kcal/mol than the template compound and gefitinib, the control, respectively. The ADMET property assessment of these newly designed EGFR inhibitors indicated that they were orally bioavailable with good absorption, distribution, metabolism, and excretory properties with no toxicity. And for their drug-likeness, they were seen to have a higher molecular weight which might be as a result of halo-phenyl-amino ring attachments. Based on this finding, halo-phenyl-amino rings might be responsible for the inhibitory activities of these newly designed compounds.
The six newly designed EGFR inhibitors were found to have higher binding affinities toward their target EGFR receptor than the template compound and gefitinib which was used as the control in this research. They were seen to have good ADMET and drug-like properties which indicate that they might be orally bioavailable. Furthermore, according to their synthetic accessibility score, they can be easily synthesized in the laboratory because the values were found to be less than five which fall within the easy portion of the scale. Therefore, this research recommends that these newly designed EGFR inhibitors should be synthesized most especially those with higher binding affinities, good ADMET, and drug-likeness properties than the template compound.