部分取代芳烃发光菌毒性的HQSAR分析

采用分子全息定量构效关系(Holographic QSAR)对47个取代芳烃的发光菌生物毒性与化学分子结构之间的关系进行了研究和分析.分子全息表征方法所构建的结构活性模型比传统的理化表征和其他基于碎片的低连接性表征方法优越,由模型所得到的交互检验预测结果拟合相关系数为Q2=0.904.模型的质量随碎片大小而改变,碎片范围变化较大.因为分子全息方法表征的是有机污染物与配体之间相互作用的内在信息,所以这种相对简单的分子碎片表征方法能够反映出分子结构的细微性质.

演化自适应建模在QSAR研究中的应用

演化自适应建模利用自然选择的方法处理建模和模型优化问题,通过在模型空间中搜索问题的解来揭示输入与输出数据间存在的相关关系并以此来估计和外推系统的行为,该方法用于QSAR研究,具有稳定、适应性强、无需问题的背景知识等优点,可以获得多个较为准确描述药物构效关系的模型,既可以是线性模型,也可以是非线性模型,但对于自变量较多的问题,该方法的编码方式可能使效率下降。

Molecular Modeling and Design of Arylthioindole Derivatives as Tubulin Inhibitors

Three-dimensional quantitative structure activity relationship （3D-QSAR） and docking studies of a series of arylthioindole derivatives as tubulin inhibitors against human breast cancer cell line MCF-7 have been carried out. An optimal 3D-QSAR model from the comparative molecular field analysis （CoMFA） for training set with significant statistical quality （R2=0.898） and predictive ability （q2=0.654） was established. The same model was further applied to predict pIC50 values of the compounds in test set, and the resulting predictive correlation coefficient R2（pred） reaches 0.816, further showing that this CoMFA model has high predictive ability. Moreover, the appropriate binding orientations and conformations of these compounds interacting with tubulin are located by docking study, and it is very interesting to find the consistency between the CoMFA field distribution and the 3D topology structure of active site of tubulin. Based on CoMFA along with docking results, some important factors improving the activities of these compounds were discussed in detail and were summarized as follows： the substituents R3-R5 （on the phenyl ring） with higher electronegativity, the substituent R6 with higher eleetropositivity and bigger bulk, the substituent R7 with smaller bulk, and so on. In addition, five new compounds with higher activities have been designed. Such results can offer useful theoretical references for experimental works.

Synthesis,algal inhibition activities and QSAR studies of novel gramine compounds containing ester functional groups

2,5,6-Tribromo-l-methylgramine （TBG）, isolated from bryozoan Zoobotryon pellucidum was shown to be very efficient in preventing recruitment of larval settlement. In order to improve the compatibility of TBG and its analogues with other ingredients in antifouling paints, structural modification of TBG was focused mainly on halogen substitution and N-substitution. Two halogen-substitute gramines and their derivatives which contain ester functional groups at N-position of gramines were synthesized. Algal inhibition activities of the synthesized compounds against algae Nitzschia cIosterium were evaluated and the Median Effective Concentration （EC50） range was 1.06-6.74 lag ml^-1. Compounds that had a long chain ester group exhibited extremely high antifouling activity. Quantitive Structure Activity Relationship （QSAR） studies with multiple linear regression analysis were applied to fred correlation between different calculated molecular descriptors and biological activity of the synthesized compounds. The results show that the toxicity （log （I/EC50）） is correlated well with the partition coefficient log P. Thus, these products have potential function as antifouling agents.

3D-QSAR and action mechanism of potential dual inhibitors towards AP-1 and NF-κB

Three-dimensional quantitative structure-activity relationship （3D-QSAR） and docking studies of a series of novel dioxopyrrolinyl-amino-pyrimidine derivatives, which are potential dual inhibitors mediating a transcriptional activation towards protein-1 （AP-1） and nuclear factor kappa B （NF-κB）, have been carried out. The QS, AR models established by comparative molecular field analysis （CoMFA） and comparative molecular similarity index analysis （CoMSIA） show a good predictive ability with cross-validated coefficients q2 of 0.644 and 0.636, respectively. The docking result shows that there are quite lower average values of the flexible and rigid energy scores on the selected binding sites, meanwhile, it further shows that the binding sites just fall on the joint regions between AP-1 （and NF-κB） and DNA. The reason that these analogues have inhibition function towards AP-I and NF-κB is that their existence on these joint regions can effectively prevent free AP-I and NF-κB from binding to DNA. These results can offer a valuable theoretical reference to the pharmaceutical molecular design as well as the action mechanism analysis.

3D-QSAR and docking studies on 2-arylbenzoxazole and linker-Y transthyretin amyloidogenesis inhibitors

Transthyretin(TTR),a plasma protein with a tetramer structure,could form amyloid fibril associated with several human diseases through the dissociation of tetramer and the misfolding of monomer.These amyloidogenesis can be inhibited by small molecules which bind to the central channel of TTR.A number of small molecules like 2-arylbenzoxazoles(ABZ)analogues are proposed as promising therapeutic strategy to treat amyloidosis.In this work,comparative molecular field analysis(CoMFA)and comparative molecular similarity indices analysis(CoMSIA)three-dimensional quantitative structure-activity relationship(3D-QSAR)and docking studies were performed on series of 2-arylbenzoxazoles(ABZ)and linker-Y analogues to investigate the inhibitory activities of TTR amyloidogenesis at atomic level.Significant correlation coefficients for ABZ series(CoMFA,r2=0.877,q2=0.431;CoMSIA,r2=0.836,q2=0.447)and those for linker-Y series(CoMFA,r2=0.828,q2=0.522;CoMSIA,r2=0.800,q2=0.493)were obtained,and the generated models were validated using test sets.In addition,docking studies on 6 compounds binding to TTR were performed to analyze the forward or reverse binding mode and interactions between molecules and TTR.These results from 3D-QSAR and docking studies have great significance for designing novel TTR amyloidogenesis inhibitors in the future.