Identification and Evaluation of Phytochemicals as Potential Inhibitors for Lung Cancer Targeting EGFR Exon-19 Deletion: A Comprehensive Study Utilizing Computational Biology Approaches

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 80% of all lung cancer cases. Epidermal growth factor receptor (EGFR) exon-19 deletion mutations are mutations of EGFR most commonly found in (NSCLC). Even though there are many EGFR inhibitor medications on the market, prolonged use of these medications causes resistance. Therefore, the goal of the current study was to screen for possible inhibitors using computer-aided drug design approaches. Initial virtual screening for 31 anti-cancer compounds was performed against the EGFR exon-19 deletion mutated protein. Molecular docking was conducted to understand their affinities compared to the control inhibitor, Gefitinib. The ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions were performed to assess the pharmacokinetics and safety of the best-performing compounds. The best candidates were further investigated through 100 ns molecular dynamics (MD) simulations to evaluate the stability of the interactions with the target protein. Among all compounds, seven compounds showed higher binding affinity compared to Gefitinib (control drug). Following favorable ADME and toxicity predictions, Epigallocatechin Gallate, Kaempferol, and Apigenin are selected as the top candidates. Finally, 100ns MD simulations revealed stable interactions of these compounds with the EGFR mutant in comparison to Gefitinib. Our findings suggest that these naturally derived compounds could serve as potential therapeutic agents in the treatment of NSCLC. However, further validation through in vitro and in vivo studies is necessary to confirm the efficacy of these compounds.

非小细胞肺癌（non-small cell lung cancer, NSCLC）是临床最常见的肺癌亚型，约占全部肺癌病例的80%。表皮生长因子受体（epidermal growth factor receptor, EGFR）19号外显子缺失突变是NSCLC患者中最为频发的EGFR突变类型。尽管当前市场上已获批多款EGFR抑制剂类药物，但长期用药会导致肿瘤产生耐药性。为此，本研究依托计算机辅助药物设计手段，开展潜在EGFR抑制剂的筛选工作。研究首先针对EGFR 19号外显子缺失突变蛋白，对31种抗癌化合物进行了虚拟筛选。通过分子对接实验，对比阳性对照药物吉非替尼（Gefitinib），评估各化合物与靶蛋白的结合亲和力。随后对表现最优的化合物开展ADMET（吸收、分布、代谢、排泄及毒性）预测，以表征其药代动力学特征与安全性。针对筛选得到的最佳候选化合物，进一步开展100 ns分子动力学（molecular dynamics, MD）模拟，以考察其与靶蛋白结合相互作用的稳定性。受试化合物中共有7种的结合亲和力优于吉非替尼。经ADME及毒性预测表现良好的表没食子儿茶素没食子酸酯（Epigallocatechin Gallate）、山奈酚（Kaempferol）与芹菜素（Apigenin）被选为最优候选化合物。最终的100 ns分子动力学模拟结果显示，相较于吉非替尼，这三种化合物与突变型EGFR的结合相互作用稳定性更优。本研究结果表明，上述天然来源的化合物可作为治疗NSCLC的潜在候选治疗药物。但仍需借助体外（in vitro）与体内（in vivo）实验开展进一步验证，以确认这些化合物的治疗功效。