Srivastava Vivek, Kumar Ashutosh, Mishra Bhartendu Nath, Siddiqi Mohammad Imran
Department of biotechnology, Institute of engineering and technology, Sitapur road, Lucknow 21.
Bioinformation. 2008 Jun 27;2(9):384-91. doi: 10.6026/97320630002384.
Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (78 compounds) of 2, 4-diamino-5-methyl-5-deazapteridine (DMDP) derivatives as potent anticancer agents. The best prediction were obtained with a CoMFA standard model (q(2) = 0.530, r(2) = 0.903) and with CoMSIA combined steric, electrostatic, hydrophobic and hydrogen bond donor fields (q(2) = 0.548, r(2) = 0.909). Both models were validated by a test set of ten compounds producing very good predictive r(2) values of 0.935 and 0.842, respectively. CoMFA and CoMSIA contour maps were then used to analyze the structural features of ligands to account for the activity in terms of positively contributing physiochemical properties such as steric, electrostatic, hydrophobic and hydrogen bond donor fields. The resulting contour maps produced by the best CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series of analogs. This study suggests that the highly electropositive substituents with low steric tolerance are required at 5 position of the pteridine ring and bulky electronegatve substituents are required at the meta-position of the phenyl ring. The information obtained from CoMFA and CoMSIA 3-D contour maps can be used for the design of deazapteridine-based analogs as anticancer agents.
基于三维定量构效关系（3D-QSAR）研究，对一系列（78种化合物）作为强效抗癌剂的2,4-二氨基-5-甲基-5-脱氮蝶啶（DMDP）衍生物进行了比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）。使用CoMFA标准模型（q(2)=0.530，r(2)=0.903）以及结合了空间、静电、疏水和氢键供体场的CoMSIA模型（q(2)=0.548，r(2)=0.909）获得了最佳预测结果。两个模型均通过一组十种化合物的测试集进行验证，分别产生了非常好的预测r(2)值0.935和0.842。然后使用CoMFA和CoMSIA等高线图分析配体的结构特征，以根据诸如空间、静电、疏水和氢键供体场等具有正向贡献的物理化学性质来解释活性。由最佳CoMFA和CoMSIA模型生成的等高线图用于识别该系列类似物中与生物活性相关的结构特征。该研究表明，在蝶啶环的5位需要具有低空间耐受性的高正电取代基，而在苯环的间位需要大体积的负电取代基。从CoMFA和CoMSIA三维等高线图获得的信息可用于设计基于脱氮蝶啶的类似物作为抗癌剂。
