An outlook of docking analysis and structure-activity relationship of pyrimidine-based analogues as EGFR inhibitors against non-small cell lung cancer (NSCLC).

IF 2.7 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Rohit Pal, Ghanshyam Teli, Sindhuja Sengupta, Lalmohan Maji, Gurubasavaraja Swamy Purawarga Matada
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引用次数: 0

Abstract

Almost 80% of lung cancer diagnoses each year correspond to non-small cell lung cancer (NSCLC). The percentage of NSCLC with EGFR overexpression ranges from 40% to 89%, with squamous tumors showing the greatest rates (89%) and adenocarcinomas showing the lowest rates (41%). Therefore, in NSCLC therapy, blocking the EGFR-driven pathway by inhibiting the intracellular tyrosine kinase domain of EGFR has exhibited significant improvement. In this view, several small molecules particularly pyrimidine/fused pyrimidine scaffolds were intended for molecular hybridization to develop EGFR-TK inhibitors. However, the associated limitation such as resistance and genetic mutation along with adverse effects, constrained the long-term treatment and effectiveness of such medication. Therefore, in recent years, pyrimidine derivatives were uncovered as potential EGFR TKIs. The present review summarised the research progress of EGFR TKIs to dazed structure-activity relationship, biological evaluation, and comparative docking studies of pyrimidine compounds. We have added the comparative docking analysis followed by the molecular simulation study against the four different PDBs of EGFR to strengthen the already existing research. Docking analysis unfolded that compound 14 resulted as noticeable with all different PDB and managed to interact with some of the crucial amino acid residues. From a future perspective, researchers must develop a more selective inhibitor, that can selectively target the mutation. Our review will support medicinal chemists in the direction of the development of novel pyrimidine-based EGFR TKIs.Communicated by Ramaswamy H. Sarma.

嘧啶类类似物作为非小细胞肺癌(NSCLC)表皮生长因子受体(EGFR)抑制剂的对接分析和结构-活性关系展望。
在每年确诊的肺癌中,近 80% 属于非小细胞肺癌(NSCLC)。表皮生长因子受体(EGFR)过表达的非小细胞肺癌比例从 40% 到 89% 不等,其中鳞状肿瘤的比例最高(89%),腺癌的比例最低(41%)。因此,在 NSCLC 治疗中,通过抑制表皮生长因子受体的胞内酪氨酸激酶结构域来阻断表皮生长因子受体驱动的通路已显示出显著的疗效。有鉴于此,一些小分子药物,特别是嘧啶/融合嘧啶支架被用于分子杂交,以开发表皮生长因子受体-酪氨酸激酶抑制剂。然而,耐药性和基因突变等相关限制以及不良反应制约了此类药物的长期治疗和有效性。因此,近年来,嘧啶衍生物被认为是潜在的表皮生长因子受体 TKIs。本综述总结了 EGFR TKIs 的研究进展,包括嘧啶类化合物的结构-活性关系、生物学评价和比较对接研究。为了加强已有的研究,我们增加了针对四个不同的表皮生长因子受体 PDB 的比较对接分析和分子模拟研究。对接分析结果显示,化合物 14 与所有不同的 PDB 都有明显的相互作用,并能与一些关键的氨基酸残基相互作用。从未来的角度来看,研究人员必须开发出一种更具选择性的抑制剂,能够选择性地针对突变。我们的综述将为药物化学家开发新型嘧啶类表皮生长因子受体抑制剂提供支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Biomolecular Structure & Dynamics
Journal of Biomolecular Structure & Dynamics 生物-生化与分子生物学
CiteScore
8.90
自引率
9.10%
发文量
597
审稿时长
2 months
期刊介绍: The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.
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