新型吉非替尼类似物对21种靶蛋白的计算机抗癌活性的设计和评价

Supriti Khan Ushna , Ananta Kumar Das
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摘要

随着时间的推移,证据表明已经发现了许多药物,以及计算机建模或“计算机方法”,以了解抗癌蛋白质如何相互作用。吉非替尼,一种喹唑啉,通过附着在其atp结合位点上抑制EGFR酪氨酸激酶。为了了解新的吉非替尼类似物靶向癌症的有效性,本研究使用了分子对接和ADMET分析。本研究利用autodock工具对21种抗癌靶蛋白进行对接。利用基于配体的设计创造了20个新的类似物,前沿分子轨道分析表明,设计的分子更具活性和更柔软。根据对接研究,大多数设计的分子具有比吉非替尼更高的结合亲和力。此外,化合物C-4、C-5、C-7、C-9、C-11、C-12和C-14对两个以上的靶标具有较强的亲和力。突变靶蛋白与设计分子的对接实验表明,许多靶蛋白表现出与未突变蛋白相当的结合特性。根据对靶点的文献综述,这些分子可能有助于治疗多种癌症,包括肿瘤生长、慢性髓性白血病、慢性淋巴细胞白血病、急性髓性白血病、急性淋巴性白血病、甲状腺癌和唾液腺癌。结合亲和力、药物相似度评分等ADMET实验表明,设计的分子将具有更显著的抗癌活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Design, and evaluation of in-silico anti-cancer activity of novel gefitinib analogues against 21 target proteins
Over time, evidence suggests that numerous drugs have been discovered, and computer modelling, or the "In silico method", to understand how anti-cancer proteins interacted. Gefitinib, a quinazoline, inhibits the EGFR tyrosine kinase by attaching to its ATP-binding site. In order to find out how effective new gefitinib analogues are at targeting cancer, this study used molecular docking and ADMET analysis. In this study, the 21 anti-cancer target proteins were utilized to perform docking by using autodock tools. Twenty new analogues were created using ligand-based design, and frontier molecular orbital analysis revealed that the designed molecules are more reactive and softer. The majority of the designed molecules have higher binding affinities than gefitinib, according to the docking studies. Additionally, the analysis revealed that the compounds C-4, C-5, C-7, C-9, C-11, C-12, and C-14 have superior affinity to more than two targets. Docking experiments of the mutated target proteins with designed molecules demonstrate that many target proteins exhibit binding properties comparable to those of the unmutated proteins. According to the literature review on targets, these molecules may be helpful in the treatment of many cancers, including tumour growth, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphoid leukemia, thyroid cancers, and salivary gland cancers. It was shown by the binding affinity, drug similarity score, and other ADMET experiments that the designed molecules will have more significant anti-cancer activity.
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