Background: Colorectal cancer (CRC) is considered the second deadliest cancer in the world. One of the reasons for the occurrence of this cancer is the deregulation of the Epidermal Growth Factor Receptor (EGFR), which plays a critical role in regulating cell division, persistence, differentiation, and migration. The overexpression of the EGFR protein leads to its dysregulation and causes CRC. Objective: Hence, this work aims to identify and validate novel EGFR inhibitors for the treatment of colorectal cancer employing various computer aided techniques such as pharmacophore modeling, docking, molecular dynamic simulation and Quantitative Structure-Activity Relationship (QSAR) analysis. Methods: In this work, a shared-featured ligand-based pharmacophore model was generated using the known inhibitors of EGFR. The best model was validated and screened against ZincPharmer and Maybridge databases, and 143 hits were obtained. Pharmacokinetic and toxicological properties of these hits were studied, and the acceptable ligands were docked against EGFR. The best five protein-ligand complexes with binding energy less than -5 kcal/mol were selected. The molecular dynamic simulation studies of these complexes were conducted for 100 nanoseconds (ns), and the results were analyzed. The biological activity of this ligand was calculated using QSAR analysis. Results: The best complex with Root Mean Square Deviation (RMSD) 3.429 Å and Radius of Gyration (RoG) 20.181 Å was selected. The Root Mean Square Fluctuations (RMSF) results were also found to be satisfactory. The biological activity of this ligand was found to be 1.38 μM. Conclusion: This work hereby proposes the ligand 2-((1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)oxy)-N- (1H-indol-4-yl)acetamide as a potential EGFR inhibitor for the treatment of colorectal cancer. The wet lab analysis must be conducted, however, to confirm this hypothesis.

中文翻译：

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利用药效团建模、对接、分子动力学模拟和生物活性预测鉴定用于结直肠癌靶向治疗的新型 EGFR 抑制剂


背景：结直肠癌（CRC）被认为是世界上第二大致命癌症。这种癌症发生的原因之一是表皮生长因子受体（EGFR）的失调，该受体在调节细胞分裂、持久性、分化和迁移方面发挥着关键作用。 EGFR 蛋白的过度表达导致其失调并导致 CRC。目的：因此，本工作旨在利用药效团建模、对接、分子动力学模拟和定量构效关系（QSAR）分析等各种计算机辅助技术，鉴定和验证用于治疗结直肠癌的新型 EGFR 抑制剂。方法：在这项工作中，使用已知的 EGFR 抑制剂生成了一个共享特征的基于配体的药效团模型。最佳模型经过 ZincPharmer 和 Maybridge 数据库的验证和筛选，获得了 143 个匹配结果。研究了这些命中的药代动力学和毒理学特性，并将可接受的配体与 EGFR 对接。选择结合能小于-5 kcal/mol 的最佳五个蛋白质-配体复合物。对这些配合物进行了100纳秒(ns)的分子动力学模拟研究，并对结果进行了分析。使用 QSAR 分析计算该配体的生物活性。结果：选择了均方根偏差 (RMSD) 3.429 Å 和回转半径 (RoG) 20.181 Å 的最佳配合物。均方根波动 (RMSF) 结果也令人满意。该配体的生物活性为 1.38 μM。 结论：本工作特此提出配体 2-((1,6-二甲基-4-氧代-1,4-二氢吡啶-3-基)氧基)-N-(1H-吲哚-4-基)乙酰胺作为潜在的配体EGFR抑制剂用于治疗结直肠癌。然而，必须进行湿实验室分析来证实这一假设。