IN SILICO INVESTIGATION OF 3,6-DIPHENYL-[1,2,4]TRIAZOLO[3,4-B][1,3,4]THIADIAZOLE DERIVATIVES AS EGFR MODULATORS FOR LUNG CANCER TREATMENT

Abstract

Lung cancer (LC) is the second most common malignancy in men globally. Current treatments often target hormone receptors in prostate tissue, but these therapies are associated with significant toxicity and drug resistance. To overcome these challenges, our research focuses on developing novel synthetic compounds that target the Epidermal Growth Factor Receptor (EGFR), which is frequently overexpressed or mutated in cancers like lung, colorectal, and glioblastoma. EGFR activation regulates critical cellular functions, and its aberrations can lead to uncontrolled tumor growth. This study evaluates the in silico pharmacokinetic properties (ADME), toxicity, and drug-likeness profiles of 12 synthetic compounds using computational tools such as SwissADME, ProTox-II, Molinspiration, ADMETlab, and Density Functional Theory (DFT). DFT optimization was conducted with the B3LYP method and a 6-31++G(d,p) basis set. We simulated the electrostatic potential surface and analyzed molecular stability through HOMO-LUMO calculations to assess energy gaps, chemical potential, electronegativity, hardness, and softness. Molecular docking studies, using AutoDock Vina, identified the binding affinity of these compounds against EGFR (PDB ID: 1M17). Among them, JM-19 demonstrated the highest binding affinity of −5.164 kcal/mol, outperforming previous therapeutic agents. These findings suggest that these synthetic molecules are promising candidates for further preclinical development in LC prevention and treatment.

Keywords: 

Lung Cancer, Epidermal Growth Factor Receptor, Synthetic Compounds, Drug Resistance, Pharmacokinetics, Toxicity Profiles, Drug-Likeness, Computational Tools, SwissADME, ProTox-II, Molinspiration, ADMETlab, Density Functional Theory