Lead Identification of Some Anti-Cancer Agents with Prominent Activity Against Non-small Cell Lung Cancer (NSCLC) and Structure-Based Design

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Cancer was recognised to be daunting illness and second cause of death worldwide. The death estimate caused by cancer as of 2012 was about 17% of the total deaths (which is about 8.5 million) and in 2030 will be about 13.1 million deaths. Lung cancer is one of the leading cancer problems in the globe. It was reported to cause a lot of death every year. In all types of cancer, non-small cell lung cell (NSCLC) is one of the various causes of cancer-related mortality. Therefore there is need to design more potent NSCLC therapeutic agents. The purpose of this work is to identify lead compounds among the investigated ant-cancer agents with prominent activity against NSCLC and also design new NSCLC therapeutic agents by carrying out structural modification on the best lead compound using Structure-based approach. The method employed in this research is structure-based drug design approach on some anti-cancer agents. It involves molecular docking which study how these anti-cancer agents interact in with active site of their target protein (EGFR receptor PDB code: 4ZAU) and identify which among the investigated molecules have the lowest docking score/highest binding affinity toward the target and then predict their pharmacokinetic profile. The best among them will be used as template for designing new NSCLC therapeutic agents with higher affinity toward EGFR receptor. The investigation of the binding mode of some NSCLC therapeutic agents against EGFR receptor (PDB: 4ZAU) was achieved through docking in this research. Five compounds exhibited the best docking scores among the docked ligands were compound 7, 19, 22, 27 and 34. Compound 19 and 27 under investigation were found to have the lowest docking score of -9.7 kcal/mol among the compounds under investigation. Compound 19 was seen to interact in the binding site of EGFR receptor through electrostatic interaction with LYS745 amino acid residue of the EGFR receptor, hydrophobic interaction with LYS745, VAL726, ALA743, LEU844 and LEU718 amino acid residues and hydrogen bond interaction with GLU762 (2.69145 A), ASP855 (2.78155 A) and LYS745 (3.05463 A) amino acid residues in the binding site of EGFR receptor which might be responsible for the lowest energy (highest docking score) of the ligand. The ADME/Pharmacokinetics and drug-likeness of these lead compounds and compound 27 were predicted and observed to be orally bioavailable because none of them broke more than the allowable limit by Lipinski’s RO5 filters. Compound 27 was retained and used as a template for the designing process. Thirteen (13) new NSCLC therapeutic agents were designed were designed by carrying out structural modification on methyl group attached to ‘1, 2, 4 triazolo pteridinone’ moiety and two methyl groups attached to ‘piperidin-1-yl’ of the template. The molecular docking simulation, ADME/Pharmacokinetics and drug-likeness employed on some NSCLC therapeutic agents discovered five compounds (7, 19, 22, 27 and 34) with the lowest docking scores among other compounds under investigation and found to be orally bioavailable. More so, the thirteen (13) new NSCLC therapeutic agents designed were found to have better affinity toward their target than the template. Also, these designed compounds were then compared with a control and found to be better than the control.