利用分子对接和相互作用指纹图谱研究设计表皮生长因子受体抑制剂杂环化合物

G. Rajitha
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引用次数: 0

摘要

EGFR(表皮生长因子受体)在不同类型的癌症中表达,如乳腺癌、食道癌、癌症等。由于其在癌症进展中的多方面作用,EGFR及其相关受体被认为是开发抗癌药物的有吸引力的靶点,即由靶向EGFR-ATP结合口袋的分子组成的EGFR抑制剂和靶向EGFR配体结合结构域的单克隆抗体。对于EGFR突变型非小细胞肺癌癌症患者,获得性耐药性阻碍了靶向治疗的长期疗效。尽管靶向EGFR T790M突变的第三代药物在克服对EGFR酪氨酸激酶抑制剂的获得性耐药性方面显示出了前景,但仍需要靶向第三代抑制剂获得性耐药性的第四代药物。因此,在本研究中,选择EGFR(PDB:1M17)作为靶点,对文献中现有的配体进行分子对接研究。对接配合物相互作用指纹图谱分析。对接研究表明,化合物3对所选靶标表现出良好的结合亲和力,在现有配体中XPG评分为-9.439Kcal/Mol,与标准药物厄洛替尼的评分为-9.192kcal/Mol相当。相互作用指纹分析进一步证实,最佳对接的化合物以与标准药物厄洛替尼相同的方式与Met 769和Cys 773的骨架残基显示出氢键相互作用。本研究得出结论,在选定的现有化合物中,与标准药物厄洛替尼相比,含有喹唑啉核的配体表现出良好的结合亲和力和相似的结合相互作用,这些配体可以进一步优化,以增加与选定靶标的结合亲和力及相互作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Design of Heterocyclic Compounds as Epidermal Growth Factor Receptor Inhibitors Using Molecular Docking and Interaction Fingerprint Studies
EGFR (Epidermal Growth factor receptors) expressed in different type of cancers, such as breast, esophageal, lung cancer etc. Because of their multifaceted role in cancer progression, EGFR and its related receptors have been considered as attractive targets for developing anticancer agents, i.e. EGFR inhibitors consisting molecules targeting EGFR ATP binding pocket and monoclonal antibodies targeting EGFR ligand binding domain. For patients with EGFR-mutant non-small-cell lung cancer, acquired resistance to drugs obstructs long-term therapeutic efficacy of targeted therapy. Even though third-generation medicines targeting EGFR T790M mutation have shown promise in overcoming acquired resistance to EGFR-tyrosine kinase inhibitors, fourth-generation drugs targeting acquired resistance to 3rd generation inhibitors are still needed. Hence, in present study, EGFR (PDB: 1M17) was selected as a target to perform molecular docking studies for existing ligands from literature. Interaction fingerprint analysis was applied for docked complexes. Docking studies revealed that compound 3 exhibited good binding affinity towards the selected target with XPG score-9.439Kcal/Mol among existing ligands which is comparable with that of standard drug erlotinib -9.192 Kcal/Mol. Interaction fingerprint analysis further confirmed that best docked compounds showed H-bond interaction with backbone residue of Met 769 and Cys 773 in an identical manner with that of standard drug erlotinib. Present study concludes that among selected existing compounds, the ligands containing quinazoline nucleus exhibited good binding affinity and similar binding interactions when compared with that of standard drug erlotinib and these ligands can be further optimized to increase binding affinity and interactions with the selected target.
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来源期刊
Bioscience Biotechnology Research Communications
Bioscience Biotechnology Research Communications BIOTECHNOLOGY & APPLIED MICROBIOLOGY-
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