Ligand-based virtual screening, molecular docking, QSAR and pharmacophore analysis of quercetin-associated potential novel analogs against epidermal growth factor receptor

The present study was to explore expectation and examination of therapeutic potential quercetin analogs as efficient anticancer agents against human epidermal growth factor receptor (EGFR), which is a consistent hallmark for moderating the non-small-cell lung carcinoma (NSCLC). Here, ligand-based virtual screening, pharmacophore approach and molecular docking were established as rational strategies for recognition of small analogs against the ligand binding domain of EGFR (PDB code: 1XKK). Adverse effects, toxicogenomics and pharmacokinetics reported that 10 candidates showed reliable consequences with less side effects and more efficient for target receptor. Protein–ligand interaction profiles revealed that the probable H-bonds, atomic-π contacts, salt bridges and van der Waals interactions sustain the complexity and stability of receptor structure; thus, they could complicate to generate single alteration acquired for drug resistance. <i>In silico</i> anticancer properties explain the lead scaffolds which are assumed to be flexible and experimentally proved chemicals. The overall consequences indicated that recognized leads could be utilized as reference skeletons for new inhibitors envisaging toward EGFR to ameliorate NSCLC and other malignant disorders.

本研究旨在探究槲皮素类似物作为高效抗人类表皮生长因子受体（human epidermal growth factor receptor, EGFR）抗肿瘤药物的应用前景与活性效果——EGFR是非小细胞肺癌（non-small-cell lung carcinoma, NSCLC）调控过程中的核心标志性靶点。本研究采用基于配体的虚拟筛选（ligand-based virtual screening）、药效团建模法（pharmacophore approach）与分子对接（molecular docking）作为合理筛选策略，旨在识别可靶向EGFR配体结合域（PDB编号：1XKK）的小分子衍生物。通过不良反应、毒理基因组学（toxicogenomics）与药代动力学（pharmacokinetics）分析，10个候选化合物展现出可靠的活性表现：对靶受体的抑制活性更优，且不良反应更少。蛋白质-配体相互作用谱（protein–ligand interaction profiles）分析显示，潜在的氢键（hydrogen bonds, H-bonds）、原子-π相互作用（atomic-π contacts）、盐桥（salt bridges）与范德华相互作用（van der Waals interactions）共同维持了受体结构的复杂性与稳定性，因此可有效阻碍耐药性单点突变的形成。计算机模拟（in silico）抗肿瘤活性分析表明，本次筛选得到的先导骨架具备良好的柔性，且对应的化合物已通过实验验证。整体研究结果表明，所识别的先导化合物可作为参考骨架，用于开发靶向EGFR的新型抑制剂，以改善非小细胞肺癌及其他恶性肿瘤的治疗效果。