对32个碳环类神经氨酸酶抑制剂进行了二维定量构效关系(2D-QSAR)研究,27个作为训练集,5个作为测试集,对计算所得的理化和量化参数进行预选后,采用偏最小二乘法(Partial least squares,PLS)建立预测模型,该模型的非交叉法验证相关系数为R...对32个碳环类神经氨酸酶抑制剂进行了二维定量构效关系(2D-QSAR)研究,27个作为训练集,5个作为测试集,对计算所得的理化和量化参数进行预选后,采用偏最小二乘法(Partial least squares,PLS)建立预测模型,该模型的非交叉法验证相关系数为R2=0.976 2,交叉法验证相关系数为R2CV=0.965 1;以此预测模型对测试集的5个化合物的活性进行预测,相关系数为R2pred=0.877 9,表明该模型具有较强的预测能力,可以指导对已有的流感药物进行化学修饰,并能指导新的神经氨酸酶抑制剂的设计及合成.展开更多
The Two-dimensional Quantitative Structure-activity Relationship （2D-QSAR） of a series of novel norcantharidin analogues, which exhibit hnhibitory activities of protein phosphatase 1 and 2A （PP1 and PP2A）, has bee...The Two-dimensional Quantitative Structure-activity Relationship （2D-QSAR） of a series of novel norcantharidin analogues, which exhibit hnhibitory activities of protein phosphatase 1 and 2A （PP1 and PP2A）, has been studied with a combined method of ab initio （I/F）, molecular mechanics （MM＋） and statistics. The established 2D-QSAR model （Eq. 1） for PP1 shows a reasonable regressive performance （R2= 0.749）, and the hydrophobic property of this molecule plays a decisive role in determining the inhibitory activity of PP1. In addition, the established 2D-QSAR model （Eq. 2） for PP2A also shows an acceptable regressive performance （R2= 0.701）, and the dipole moment of the molecule determines the inhibitory activity of PP2A.展开更多
Quantitative structure activity relationship （QSAR） studies were performed on 45 anthranilic acid derivatives for their potent allosteric inhibition activities of HCV NSSB polymerase. Genetic algorithm based genetic...Quantitative structure activity relationship （QSAR） studies were performed on 45 anthranilic acid derivatives for their potent allosteric inhibition activities of HCV NSSB polymerase. Genetic algorithm based genetic function approximation （GFA） method of variable selection was used to generate the model. Highly statistically significant model with r^2 = 0.966 and r^2cv = 0.951 was obtained when the number of descriptors in the equation was set to 5. High r^2pred value of 0.884 indicates the good predictive power of the best model. Spatial descriptors of radius of gyration （RadOfGration）, molecular volume （Vm）, length of molecule in the z dimension （Shadow-Zlength）, thermodynamic descriptors of the octanol/water partition coefficient （LogP） and molecular refractivity index （MR） showed enormous contributions to HCV NS5B polymerase inhibition. The validation of the model was done by leave-one-out （LOO） test, randomization tests and external test set prediction. The model gives insight on indispensable structural requirements for the activity and can be used to design more potent analogs against HCV NSSB polymerase.展开更多
The geometry structures of 6 triazolone compounds containing benzenesulfonic amide were fully optimized with DFT （Density Functional Theory） method at the B3LYP/6-31G level, and the structural and electronic paramet...The geometry structures of 6 triazolone compounds containing benzenesulfonic amide were fully optimized with DFT （Density Functional Theory） method at the B3LYP/6-31G level, and the structural and electronic parameters of the compounds were calculated. The hydrophobic and topological parameters of the title compounds were calculated by HyperChem software. The mono- and bi-parametric models between the parameters and biological activity of the compounds were analyzed by Multiple Linear Regression method based on Hansch-Fujita model. The results show that the activities of the title compounds were increased with higher hydrophobic property logP and molecular volume V, lower molecular energy ETOTAL and electronegative of benzene ring Qph.展开更多
The quantitative structure-activity relationship （QSAR） of 14 phenoxybenzoic acid derivatives was studied by ab initio method at the HF/6-31G level using Guassian03 software. The optimized structures together with s...The quantitative structure-activity relationship （QSAR） of 14 phenoxybenzoic acid derivatives was studied by ab initio method at the HF/6-31G level using Guassian03 software. The optimized structures together with some characteristic and electric parameters of the title compounds were obtained; some stereo-parameters were calculated by HyperChem software. Stepwise multiple regression and principal component regression methods are adopted to establish multi-parametric models between biological activity and parameters. The results indicated that the lager Ehomo, M, V and LogP, the smaller Etumo and S, and the higher biological activity. A theoretical direction was provided to synthesize some compounds with high activity.展开更多
The quantitative structure-activity relationship （QSAR） of 16 pyrazole compounds was studied by ab initio method at the HF/3-21G level using Guassian03 soft. The optimized structures together with some characteristi...The quantitative structure-activity relationship （QSAR） of 16 pyrazole compounds was studied by ab initio method at the HF/3-21G level using Guassian03 soft. The optimized structures together with some characteristic and electric parameters of the title compounds were obtained; some stereo-parameters were calculated by HyperChem software. Stepwise multiple regression method was adopted to establish bi- and tri-parametric models between biological activity and some parameters. The lager △E and logP, the higher biological activity; and the biological activity would be promoted with the smaller μ, QN and QPYRA. It provided a theory direction to synthesize some compounds with high activity.展开更多
The mechanisms of adsorption of pesticides（dimethoate, metalaxyl, atrazine, malathion and prometryn） and heavy metals（Cu, Cd, Pb, Zn and Ni） coexisting in sediments, with pesticides as target pollutants, and the i...The mechanisms of adsorption of pesticides（dimethoate, metalaxyl, atrazine, malathion and prometryn） and heavy metals（Cu, Cd, Pb, Zn and Ni） coexisting in sediments, with pesticides as target pollutants, and the influence of their main effects and double-order interaction effects were studied using the experimental design module in the Minitab software package with a 2^10-3 fractional factorial design method at resolution V. The main, double-order interaction, synergistic and antagonistic effect values of pollutant concentrations influencing the adsorption of pesticides were set as dependent variables, while various quantum chemical parameters of pesticides were set as independent variables, and two-dimensional quantitative structure activity relationship（2D-QSAR） models were established by stepwise regression to reveal the adsorption mechanisms of pesticides in a composite contamination system. The main effects of pollutants concentration played the primary role in the adsorption of dimethoate and malathion（the rates of contributions were 53.54% and 56.46%, respectively）, while double-order interaction effects were primarily responsible for metalaxyl, atrazine and prometryn adsorption（the rates of contributions were 79.05%, 60.21% and 57.89%, respectively） in the pesticide/heavy metals coexisting sediment system. The synergistic effects of the main effects and double-order interaction effects of pollutants concentration（synergistic effects） played a leading role in adsorption of malathion and prometryn（the rates of contributions were 70.61% and 69.61%, respectively）, while an- tagonistic effects of the main effects and double-order interaction effects of pollutants（antagonistic effects） played a dominant role in the adsorption of dimethoate, metalaxyl and atrazine（the rates of contributions were 58.82%, 56.89% and 58.24%, respectively）. Moreover, the correlation coefficient value（R2） ranged from 0.986 to 0.999（〉0.8783） in the 2D-QSAR model, while the standard deviation（SD） ranged from 0.006 to 0.066 and the Ftest values were 22.684-199.544, indicating the model has good predictive ability and fit. The 2D-QSAR model revealed a significant correlation（P=0.05） between the main effects of pollutants concentrations on pesticides adsorption（main effect values） and the most positive hydrogen atomic charge（qa＋）, the highest occupied molecular orbital energy（EHOMO） and the dipole moment（μ）. Furthermore, double-order interaction effect values of pollutant concentrations influenced the adsorption of pesticides（double-order interaction effect values）, and the most positive atomic charge（q＋）, qH＋, and the lowest unoccupied molecular orbital energy（ELMO） were significantly correlated. The qw, EHOMO and μ of pesticides were found to be significant factors promoting pesticides adsorption, while the q＋ and ELVMO of pesticides were significant inhibiting factors（P=0,05）. Overall, this study provides a theoretical basis for further realization of combined pollution control of pesticide pollutants in complex environmental systems.展开更多
HIV-1整合酶(integrase,IN)是病毒复制过程的关键酶,已被证实是开发抗HIV-1药物的一个理想靶标。针对48个喹诺酮酸类整合酶链转移抑制剂(integrasestrandtransfer inhibitors, INSTIs),利用遗传函数逼近法(genetic function approximati...HIV-1整合酶(integrase,IN)是病毒复制过程的关键酶,已被证实是开发抗HIV-1药物的一个理想靶标。针对48个喹诺酮酸类整合酶链转移抑制剂(integrasestrandtransfer inhibitors, INSTIs),利用遗传函数逼近法(genetic function approximation, GFA)构建10个抑制活性与优选的分子结构描述符之间的二维定量构效关系(2D-QSAR)模型,从中优选出最佳的模型并对其进行验证,据此探究影响抑制剂生物活性的主要分子微观结构因素,希冀为其进一步结构优化提供理论指导。所建立的最优2D-QSAR模型的非交叉验证相关系数R^2为0.8903,交叉验证相关系数Q^2为0.8213,表明该模型具有较高的预测能力和明显的统计学意义。该研究表明,喹诺酮酸类INSTIs的生物活性主要受Jurs_RPCG、Shadow_nu、BIC、ALogP、Dipole_X以及Dipole_Y描述符的影响,为其进一步结构修饰,开发高效抗HIV-1药物奠定了理论基础。展开更多
Enhancer of Zeste homolog 2（EZH2） is closely correlated with malignant tumor and regarded as a promising target to treat B-cell lymphoma. In our research, the molecular docking and three-dimensional quantitative str...Enhancer of Zeste homolog 2（EZH2） is closely correlated with malignant tumor and regarded as a promising target to treat B-cell lymphoma. In our research, the molecular docking and three-dimensional quantitative structure-activity relationships（3D-QSAR） studies were performed on a series of pyridone-based EZH2 compounds. Molecular docking allowed us to study the critical interactions at the binding site of EZH2 protein with inhibitors and identify the practical conformations of ligands in binding pocket. Moreover, the docking-based alignment was applied to derive the reliable 3D-QSAR models. Comparative molecular field analysis（CoMFA） and comparative molecular similarity indices analysis（CoMSIA） provided available ability of visualization. All the derived 3D-QSAR models were considered to be statistically significant with respect to the internal and external validation parameters. For the CoMFA model, q^2 = 0.649, r^2 = 0.961 and r^2 pred = 0.877. For the CoMSIA model, q^2 = 0.733, r^2 = 0.980 and r^2 pred = 0.848. With the above arguments, we extracted the correlation between the biological activity and structure. Based on the binding interaction and 3D contour maps, several new potential inhibitors with higher biological activity predicted were designed, which still awaited experimental validation. These theoretical conclusions could be helpful for further research and exploring potential EZH2 inhibitors.展开更多
Methetraxate(MTX),a classical dihydrofolate reductase inhibitor,was a successful clinical antitumor agent,having potent inhibitory activities to several kinds of tumors.Unfortunately,the cancer cellks were easier to p...Methetraxate(MTX),a classical dihydrofolate reductase inhibitor,was a successful clinical antitumor agent,having potent inhibitory activities to several kinds of tumors.Unfortunately,the cancer cellks were easier to produce resistance to MTX which ended in the failure of chemotherapy.In order to overcome the resistance of tumor cells,a new kind of dihydrofolate reductase inhibitors called nonclassical antifolate including triazines,pyrimidines and quinazolines were designed and synthesized.Because of the different antitumor mechanisms between the two kinds of compunds,the cancer cells resistant to MTX may still be sensitive to the nonclassical antifolate.According to this theory,some nonclassical antifolate 2,4-diamino-5-methyl-6-(substituted benzylamino)quinazolines with the general structure shown in FIg.1 were synthesized and their antitumor activities were determined in this thesis.展开更多
基金supported by the China Scholarship Council (CSC [2006] No. 3085)
文摘The Two-dimensional Quantitative Structure-activity Relationship （2D-QSAR） of a series of novel norcantharidin analogues, which exhibit hnhibitory activities of protein phosphatase 1 and 2A （PP1 and PP2A）, has been studied with a combined method of ab initio （I/F）, molecular mechanics （MM＋） and statistics. The established 2D-QSAR model （Eq. 1） for PP1 shows a reasonable regressive performance （R2= 0.749）, and the hydrophobic property of this molecule plays a decisive role in determining the inhibitory activity of PP1. In addition, the established 2D-QSAR model （Eq. 2） for PP2A also shows an acceptable regressive performance （R2= 0.701）, and the dipole moment of the molecule determines the inhibitory activity of PP2A.
基金supported by the National Natural Science Foundation of China (No. 30500339)Natural Science Foundation of Zhejiang Province (NO.Y407308)the Sprout Talented Project Program of Zhejiang Province (No. 2008R40G2020019)
文摘Quantitative structure activity relationship （QSAR） studies were performed on 45 anthranilic acid derivatives for their potent allosteric inhibition activities of HCV NSSB polymerase. Genetic algorithm based genetic function approximation （GFA） method of variable selection was used to generate the model. Highly statistically significant model with r^2 = 0.966 and r^2cv = 0.951 was obtained when the number of descriptors in the equation was set to 5. High r^2pred value of 0.884 indicates the good predictive power of the best model. Spatial descriptors of radius of gyration （RadOfGration）, molecular volume （Vm）, length of molecule in the z dimension （Shadow-Zlength）, thermodynamic descriptors of the octanol/water partition coefficient （LogP） and molecular refractivity index （MR） showed enormous contributions to HCV NS5B polymerase inhibition. The validation of the model was done by leave-one-out （LOO） test, randomization tests and external test set prediction. The model gives insight on indispensable structural requirements for the activity and can be used to design more potent analogs against HCV NSSB polymerase.
基金This work was supported by talents in University (NCET-04-0649)the Natural Science Foundation of Shandong Province (Y2006B07, Z2006B01)
文摘The geometry structures of 6 triazolone compounds containing benzenesulfonic amide were fully optimized with DFT （Density Functional Theory） method at the B3LYP/6-31G level, and the structural and electronic parameters of the compounds were calculated. The hydrophobic and topological parameters of the title compounds were calculated by HyperChem software. The mono- and bi-parametric models between the parameters and biological activity of the compounds were analyzed by Multiple Linear Regression method based on Hansch-Fujita model. The results show that the activities of the title compounds were increased with higher hydrophobic property logP and molecular volume V, lower molecular energy ETOTAL and electronegative of benzene ring Qph.
基金This work was supported by the Natural Science Foundation of Fujian Province (X0650070)
文摘The quantitative structure-activity relationship （QSAR） of 14 phenoxybenzoic acid derivatives was studied by ab initio method at the HF/6-31G level using Guassian03 software. The optimized structures together with some characteristic and electric parameters of the title compounds were obtained; some stereo-parameters were calculated by HyperChem software. Stepwise multiple regression and principal component regression methods are adopted to establish multi-parametric models between biological activity and parameters. The results indicated that the lager Ehomo, M, V and LogP, the smaller Etumo and S, and the higher biological activity. A theoretical direction was provided to synthesize some compounds with high activity.
基金talents in University (NCET-04-0649)the Natural Science Foundation of Shandong Province (Y2006B07, Z2006B01)
文摘The quantitative structure-activity relationship （QSAR） of 16 pyrazole compounds was studied by ab initio method at the HF/3-21G level using Guassian03 soft. The optimized structures together with some characteristic and electric parameters of the title compounds were obtained; some stereo-parameters were calculated by HyperChem software. Stepwise multiple regression method was adopted to establish bi- and tri-parametric models between biological activity and some parameters. The lager △E and logP, the higher biological activity; and the biological activity would be promoted with the smaller μ, QN and QPYRA. It provided a theory direction to synthesize some compounds with high activity.
文摘The mechanisms of adsorption of pesticides（dimethoate, metalaxyl, atrazine, malathion and prometryn） and heavy metals（Cu, Cd, Pb, Zn and Ni） coexisting in sediments, with pesticides as target pollutants, and the influence of their main effects and double-order interaction effects were studied using the experimental design module in the Minitab software package with a 2^10-3 fractional factorial design method at resolution V. The main, double-order interaction, synergistic and antagonistic effect values of pollutant concentrations influencing the adsorption of pesticides were set as dependent variables, while various quantum chemical parameters of pesticides were set as independent variables, and two-dimensional quantitative structure activity relationship（2D-QSAR） models were established by stepwise regression to reveal the adsorption mechanisms of pesticides in a composite contamination system. The main effects of pollutants concentration played the primary role in the adsorption of dimethoate and malathion（the rates of contributions were 53.54% and 56.46%, respectively）, while double-order interaction effects were primarily responsible for metalaxyl, atrazine and prometryn adsorption（the rates of contributions were 79.05%, 60.21% and 57.89%, respectively） in the pesticide/heavy metals coexisting sediment system. The synergistic effects of the main effects and double-order interaction effects of pollutants concentration（synergistic effects） played a leading role in adsorption of malathion and prometryn（the rates of contributions were 70.61% and 69.61%, respectively）, while an- tagonistic effects of the main effects and double-order interaction effects of pollutants（antagonistic effects） played a dominant role in the adsorption of dimethoate, metalaxyl and atrazine（the rates of contributions were 58.82%, 56.89% and 58.24%, respectively）. Moreover, the correlation coefficient value（R2） ranged from 0.986 to 0.999（〉0.8783） in the 2D-QSAR model, while the standard deviation（SD） ranged from 0.006 to 0.066 and the Ftest values were 22.684-199.544, indicating the model has good predictive ability and fit. The 2D-QSAR model revealed a significant correlation（P=0.05） between the main effects of pollutants concentrations on pesticides adsorption（main effect values） and the most positive hydrogen atomic charge（qa＋）, the highest occupied molecular orbital energy（EHOMO） and the dipole moment（μ）. Furthermore, double-order interaction effect values of pollutant concentrations influenced the adsorption of pesticides（double-order interaction effect values）, and the most positive atomic charge（q＋）, qH＋, and the lowest unoccupied molecular orbital energy（ELMO） were significantly correlated. The qw, EHOMO and μ of pesticides were found to be significant factors promoting pesticides adsorption, while the q＋ and ELVMO of pesticides were significant inhibiting factors（P=0,05）. Overall, this study provides a theoretical basis for further realization of combined pollution control of pesticide pollutants in complex environmental systems.
基金supported by the National Natural Science Foundation of China(No.81270054)the program for Outstanding Young Teachers in Higher Education Institutions of Guangdong Province(No.Yq2013045)
文摘Enhancer of Zeste homolog 2（EZH2） is closely correlated with malignant tumor and regarded as a promising target to treat B-cell lymphoma. In our research, the molecular docking and three-dimensional quantitative structure-activity relationships（3D-QSAR） studies were performed on a series of pyridone-based EZH2 compounds. Molecular docking allowed us to study the critical interactions at the binding site of EZH2 protein with inhibitors and identify the practical conformations of ligands in binding pocket. Moreover, the docking-based alignment was applied to derive the reliable 3D-QSAR models. Comparative molecular field analysis（CoMFA） and comparative molecular similarity indices analysis（CoMSIA） provided available ability of visualization. All the derived 3D-QSAR models were considered to be statistically significant with respect to the internal and external validation parameters. For the CoMFA model, q^2 = 0.649, r^2 = 0.961 and r^2 pred = 0.877. For the CoMSIA model, q^2 = 0.733, r^2 = 0.980 and r^2 pred = 0.848. With the above arguments, we extracted the correlation between the biological activity and structure. Based on the binding interaction and 3D contour maps, several new potential inhibitors with higher biological activity predicted were designed, which still awaited experimental validation. These theoretical conclusions could be helpful for further research and exploring potential EZH2 inhibitors.
文摘Methetraxate(MTX),a classical dihydrofolate reductase inhibitor,was a successful clinical antitumor agent,having potent inhibitory activities to several kinds of tumors.Unfortunately,the cancer cellks were easier to produce resistance to MTX which ended in the failure of chemotherapy.In order to overcome the resistance of tumor cells,a new kind of dihydrofolate reductase inhibitors called nonclassical antifolate including triazines,pyrimidines and quinazolines were designed and synthesized.Because of the different antitumor mechanisms between the two kinds of compunds,the cancer cells resistant to MTX may still be sensitive to the nonclassical antifolate.According to this theory,some nonclassical antifolate 2,4-diamino-5-methyl-6-(substituted benzylamino)quinazolines with the general structure shown in FIg.1 were synthesized and their antitumor activities were determined in this thesis.
