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Dual potent c-Met and ALK inhibitors: from common feature pharmacophore modeling to structure based virtual screening
Journal of Receptors and Signal Transduction ( IF 2.8 ) Pub Date : 2020-03-03 , DOI: 10.1080/10799893.2020.1735418
Somayeh Pirhadi 1 , Tahereh Damghani 1, 2 , Mohammad Sadegh Avestan 3 , Shahrzad Sharifi 1
Affiliation  

Abstract Everyday plenty of people succumb to various forms of cancer across the world and it stands as one of the main reasons of death in our today’s life. Receptor tyrosine kinases (RTKs) are a class of receptors involved in cancer progression. Since aberrant signaling has critical roles in cancer, both c-Met and ALK enzymes are regarded as attractive oncology targets for therapeutic objects. A number of potent dual inhibitors of c-Met and ALK are reported in literature that in the present work we based them to construct multiple common feature pharmacophore models and then applied them for ligand-based virtual screening. The score values of the models ranged from 22.489 to 28.169. The retrieved compounds from virtual screening were subjected to the docking study and the interaction pattern of common hits between two enzymes with high predicted affinity has been investigated. To this end, common hit compound ZINC000223394281 (z1) was directed to the molecular dynamics study and the results indicated that the hydrogen bond interaction between this compound and Asp1222 was mostly stable during the equilibrium time range. The life time of hydrogen bond made between the complex of ALK and Met1199 was also stable in 63%.

中文翻译:

双效 c-Met 和 ALK 抑制剂:从共同特征药效团建模到基于结构的虚拟筛选

摘要 全世界每天都有很多人死于各种形式的癌症,它是我们当今生活中的主要死亡原因之一。受体酪氨酸激酶 (RTK) 是一类参与癌症进展的受体。由于异常信号在癌症中具有关键作用,因此 c-Met 和 ALK 酶都被视为治疗对象的有吸引力的肿瘤学靶点。文献中报道了许多有效的 c-Met 和 ALK 双重抑制剂,在目前的工作中,我们基于它们构建了多个共同特征药效团模型,然后将它们应用于基于配体的虚拟筛选。模型的得分值从 22.489 到 28.169 不等。从虚拟筛选中检索到的化合物进行对接研究,并研究了两种具有高预测亲和力的酶之间常见命中的相互作用模式。为此,共同命中化合物ZINC000223394281 (z1) 用于分子动力学研究,结果表明该化合物与Asp1222 之间的氢键相互作用在平衡时间范围内大部分是稳定的。ALK与Met1199配合物形成的氢键寿命也稳定在63%。
更新日期:2020-03-03
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