大连理工大学学报
大連理工大學學報
대련리공대학학보
JOURNAL OF DALIAN UNIVERSITY OF TECHNOLOGY
2015年
1期
7-14
,共8页
张静晓%李燕%付新梅%潘艳秋%杨凌
張靜曉%李燕%付新梅%潘豔鞦%楊凌
장정효%리연%부신매%반염추%양릉
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)
細胞凋亡誘導劑%caspase 激活作用%三維定量構效關繫(3D-QSAR)%比較分子力場法(CoMFA)%比較分子相似性指數法(CoMSIA)
세포조망유도제%caspase 격활작용%삼유정량구효관계(3D-QSAR)%비교분자력장법(CoMFA)%비교분자상사성지수법(CoMSIA)
apoptosis inducer%caspase activation%three-dimensional quantitative structure-activity relationships (3D-QSAR)%comparative molecular field analysis (CoMFA)%comparative molecular similarity indices analysis (CoMSIA)
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(3 D-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(Q2=0.51、R2ncv=0.89和R2pred=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)R2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R4取代基,以及位阻小和/或亲水的R1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.
許多抗癌藥物通過引起癌細胞的凋亡來達到治療目的,因此開髮能誘導癌細胞凋亡的藥物一直是癌癥研究的熱點.以153箇結構各異的具有 caspase-3激活作用的細胞凋亡誘導劑為研究對象,通過三維定量構效關繫(3 D-QSAR)分析,得到瞭一箇基于位阻場、靜電場、疏水場、氫鍵供體場和受體場參數的最優比較分子相似性指數法(CoMSIA)模型.該模型(Q2=0.51、R2ncv=0.89和R2pred=0.82)具有良好的內部一緻性和預測能力,通過對模型的等值線圖分析髮現:(1)R2取代基提高誘導劑活性的因素包括位阻大、負電性大、有親水性和具有氫鍵供體作用;(2)位阻適中和/或具有氫鍵供體作用的R4取代基,以及位阻小和/或親水的R1取代基對提高分子的活性是有利的;(3)N-甲基-N-苯基-1-萘胺類細胞凋亡誘導劑具有正電性的 A環3號位或C環7號位取代基,以及具有負電性的 B環1號位取代基有利于提高誘導劑的生物活性.對該模型的分析更有利于認識細胞凋亡誘導劑的分子特徵,併為設計和開髮新型細胞凋亡誘導劑提供理論指導.
허다항암약물통과인기암세포적조망래체도치료목적,인차개발능유도암세포조망적약물일직시암증연구적열점.이153개결구각이적구유 caspase-3격활작용적세포조망유도제위연구대상,통과삼유정량구효관계(3 D-QSAR)분석,득도료일개기우위조장、정전장、소수장、경건공체장화수체장삼수적최우비교분자상사성지수법(CoMSIA)모형.해모형(Q2=0.51、R2ncv=0.89화R2pred=0.82)구유량호적내부일치성화예측능력,통과대모형적등치선도분석발현:(1)R2취대기제고유도제활성적인소포괄위조대、부전성대、유친수성화구유경건공체작용;(2)위조괄중화/혹구유경건공체작용적R4취대기,이급위조소화/혹친수적R1취대기대제고분자적활성시유리적;(3)N-갑기-N-분기-1-내알류세포조망유도제구유정전성적 A배3호위혹C배7호위취대기,이급구유부전성적 B배1호위취대기유리우제고유도제적생물활성.대해모형적분석경유리우인식세포조망유도제적분자특정,병위설계화개발신형세포조망유도제제공이론지도.
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.1 5 3 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 (Q2=0.51,R2ncv=0.89 and R2pred=0.82)displays excellent inter-consistency and predictive abilities.Meanwhile,from analyzing CoMSIA contour maps,it can be concluded that (1 )the R2 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 R4 ,as well as the R1 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.