| 张静晓,李燕,付新梅,潘艳秋,杨凌.一类细胞凋亡诱导剂的结构特征研究[J].,2015,55(1):7-14 |
| 一类细胞凋亡诱导剂的结构特征研究 |
| Studies of structural feature of a series of apoptosis inducers |
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| DOI：10.7511/dllgxb201501002 |
| 中文关键词: 细胞凋亡诱导剂 caspase激活作用 三维定量构效关系(3D-QSAR) 比较分子力场法(CoMFA) 比较分子相似性指数法(CoMSIA) |
| 英文关键词: apoptosis inducer caspase activation three-dimensional quantitative structure-activity relationships (3D-QSAR) comparative molecular field analysis (CoMFA) comparative molecular similarity indices analysis (CoMSIA) |
| 基金项目:国家自然科学基金资助项目(11201049). |
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| 摘要点击次数: 1922 |
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| 中文摘要: |
| 许多抗癌药物通过引起癌细胞的凋亡来达到治疗目的，因此开发能诱导癌细胞凋亡的药物一直是癌症研究的热点．以153个结构各异的具有caspase-3激活作用的细胞凋亡诱导剂为研究对象，通过三维定量构效关系(3D-QSAR)分析，得到了一个基于位阻场、静电场、疏水场、氢键供体场和受体场参数的最优比较分子相似性指数法(CoMSIA)模型．该模型( Q 2=0.51、 R 2 ncv = 0.89和 R 2 pred =0.82)具有良好的内部一致性和预测能力，通过对模型的等值线图分析发现 (1) R 2取代基提高诱导剂活性的因素包括位阻大、负电性大、有亲水性和具有氢键供体作用；(2)位阻适中和/或具有氢键供体作用的 R 4取代基，以及位阻小和/或亲水的 R 1取代基对提高分子的活性是有利的；(3)N-甲基-N-苯基-1-萘胺类细胞凋亡诱导剂具有正电性的A环3号位或C环7号位取代基，以及具有负电性的B环1号位取代基有利于提高诱导剂的生物活性．对该模型的分析更有利于认识细胞凋亡诱导剂的分子特征，并为设计和开发新型细胞凋亡诱导剂提供理论指导． |
| 英文摘要: |
| A large number of anti-cancer agents exert their therapeutic effects through inducing apoptosis in malignant cells. Therefore, developing apoptosis-inducing drugs is always one of the hotspots in the field of cancer research. 153 structurally diverse apoptosis inducers with caspase-3 activation are studied by three-dimensional quantitative structure-activity relationships (3D-QSAR) analysis, resulting in an optimal CoMSIA (comparative molecular similarity indices analysis) model which is constructed based on the parameters of steric, electrostatic, hydrophobic, hydrogen-bond donor and receptor fields. The experimental results show that this CoMSIA model ( Q 2=0.51, R 2 ncv =0.89 and R 2 pred =0.82) displays excellent inter-consistency and predictive abilities. Meanwhile, from analyzing CoMSIA contour maps, it can be concluded that (1) the R 2 substituent with one or more features of bulk, electronegativity, hydrophilicity and H-bond donor is beneficial to the activity; (2) medium-sized and/or H-bond donor substitution of R 4, as well as the R 1 substituent with small and/or hydrophilic group can improve the activity; (3)the apoptosis inducers N-methyl-N-phenyl naphthalen-1-amines with electropositive groups in 3-position of ring-A or 7-position of ring-C, and 1-position of ring-B possessing the electronegative groups will benefit the apoptosis-inducing bio-activity. These conclusions may be helpful to understanding the molecular characteristics of apoptosis inducers, as well as providing theoretical guidance for the design and development of novel apoptosis inducers. |
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