N,N-二甲基-2-溴苯乙胺类衍生物活性与CoMFA、CoMSIA的研究

用比较分子力场分析(CoMFA)法和比较分子相似性指数分析(CoMSIA)法,建立N,N-二甲基-2-溴苯乙胺类化合物的3D-QSAR模型。CoMFA模型中,其交叉验证系数q2=0．792,传统的相关系数R2=0．955(R=0．978),相应立体场贡献为77．4％、静电场贡献为22．6％,优于文献的报导。CoMSIA研究中,其交叉验证系数q2=0．757,传统的相关系数R2=0．917 (R=0．958),其疏水场、立体场、静电场贡献依次为:42．9％、39．5％、17．6％。用两种模型分别预测检测集分子的活性,结果与实验值较吻合。说明所建的模型具有较好的预测能力。通过分析CoMFA分子场等值线图,可为优化N,N-二甲基-2-溴苯乙胺类衍生物的结构提供理论指导。     

类青蒿素抗疟活性3D-QSAR研究

采用比较分子力场分析(CoMFA)法,将40个类青蒿素的抗疟活性作了定量构效关系的研究。所得模型交叉验证系数q2为0．601,非交叉验证系数r2为0．982,标准偏差SE=0．140,F=302．246,其中立体场与静电场的贡献分别为33．0％和67．0％。CoMFA离散图表明,增大C13上取代基的体积以及增强O15上取代基的电负性等,都有利于提高化合物的抗疟活性。该模型的离散图为改造此类化合物的结构提供理论依据和研究方向。     

DNA依赖蛋白激酶抑制剂的CoMFA研究

运用比较分子力场分析方法(CoMFA),以DNA依赖蛋白激酶(DNA-PK)抑制剂分子为研究对象,建立1组对DNA依赖蛋白激酶有抑制活性化合物的三维定量构效关系(3D-QSAR)模型,探索其活性数据和三维结构参数的关系,所建最佳模型交叉验证相关系数q2=0.670,非交叉验证相关系数R2=0.993,标准偏差SD=0.053,说明该模型预测能力较好.根据CoMFA模型的三维等势图可知,小体积、电负性大的取代基团,能提高该类化合物的活性,为新型DNA-PK抑制剂分子的设计提供了理论依据.     

N，N-二甲基二2-溴苯乙胺类衍生物活性与CoMFA、CoMSIA的研究

用比较分子力场分析（CoMFA）法和比较分子相似性指数分析（CoMSIA）法，建立N，N-二甲基-2-溴苯乙胺类化合物的3D—QSAR模型。CoMFA模型中，其交叉验证系数q^2=0．792，传统的相关系数R^2=0．955（R=0．978），相应立体场贡献为77．4％、静电场贡献为22．6％，优于文献的报导。CoMSIA研究中，其交叉验证系数q^2=0．757，传统的相关系数R^2=0．917（R=0．958），其疏水场、立体场、静电场贡献依次为：42．9％、39．5％、17．6％。用两种模型分别预测检测集分子的活性，结果与实验值较吻合。说明所建的模型具有较好的预测能力。通过分析CoMFA分子场等值线图，可为优化N，N-二甲基-2-溴苯乙胺类衍生物的结构提供理论指导。     

新非核苷喹诺酮类HIV-1逆转录酶抑制剂的CoMFA研究

目的：应用比较分子力场法(COMFA)研究一系列喹诺酮类对HIV-1逆转录酶抑制活性的三维定量构效关系,为进一步抗HIV药物设计提供理论依据。方法和结果：在研究的29个化合物中,用比较分子力场法得到一个CoMFA模型,交叉验证系数为q~2=0.556,具有较高的预测能力及合理性,非交叉验证模型相关系数分别为r~2=0.998,标准偏差SE=0.044,F= 401.038；结论：此模型对设计和预测高活性的喹诺酮类HIV-1逆转录酶抑制活性的化合物有一定可靠性。     

比较分子力场法研究5,6-二氢-(9H)-吡唑[3,4-c]-1,2,4-三唑[4,3-a]吡啶类抑制剂的定量构效关系

利用比较分子力场分析法(CoMFA),以5,6-二氢-(9H)-吡唑[3,4-c]-1,2,4一三唑[4,3-a]吡啶类抑制剂为研究对象,建立一组对嗜酸性粒细胞磷酸二酯酶有抑制活性的化合物及其三维定量构效关系(3D-QSAR)模型,探索化合物活性数据和三维结构参数之间的关系.模型的交叉验证相关系数q2=0.565,非交叉验证相关系数r2=0.867,标准偏差SE=0.362,F=49.782,立体场和静电场的贡献值分别为72.7%和27.3%.该模型的预测能力较好,能够增大取代基体积和降低取代基电负性,可以提高该类化合物的活性.     

新型肟醚拟除虫菊酯化合物杀粘虫活性3D-QSAR研究

用比较分子力场分析（CoMFA）方法对50个自主设计并合成的新型芳基烷基肟醚化合物杀粘虫活性的定量构效关系进行了研究。所得模型交叉验证参数q^2为0．598，非交叉验证相关系数r^2为0．949，标准偏差SE=0．136，F=92．419，影响药效的立体场与静电场的贡献分别50．6％和49．4％。CoMFA等值线图表明化合物肟苯环对位取代基是影响其杀粘虫活性的主要因素，体积和电性增加有利于提高化合物的杀粘虫活性。该模型三维等值线图为该类化合物的结构改造提供了理论依据。     

联苯酰胺类p38αMAPK抑制剂三维定量构效关系研究

p38α丝裂原活化蛋白激酶(p38α mitogen-activated protein kinase,p38α MAPK)是治疗类风湿关节炎的最有效的靶点之一,联苯酰胺是最近新发现的一类强效、高选择性的p38α MAPK抑制剂,本文运用比较分子力场分析(CoMFA)研究21个联苯酰胺类p38αMAPK抑制剂三维定量构效关系.建立CoMFA模型的交叉验证系数q2=0.542,非交叉验证相关系数r2=0.935,统计方差比F=43.136.预测训练集和测试集化合物活性,其值和实验值非常接近,表明模型的预测能力很好.模型显示立体场和静电场对生物活性的贡献分别为78.8%和21.2%.CoMFA模型的三维等值图可为化合物的结构改造提供理论依据.     

1,2,4-oxadiazole类非季胺肟胆碱酯酶重活化剂的CoMFA研究

应用比较分子力场法(CoMFA)研究一系列1,2,4-oxadiazole非季胺肟类乙酰胆碱酯酶(AChE)重活化剂的三维定量构效关系。以肟基(-c=N-OH)部分进行有效分子重叠,得到两个不同种属的CoMFA 摸型的交叉验证系数q~2>0.5,具有一定预测能力及合理性。其中,该类化合物在复活人类体外EPMP 抑制的AChE 活性的3D-QSAR 模型中q~2=0.530,非交叉验证模型相关系数r~2=0.992,标准偏差SE=0.198,F=196.7;并依据此模型设计、预测了3个理论上具有较高活性的化合物。     

二苯基吡咯烷酮类5-HT_(2C)抑制剂三维定量构效关系的研究

目前在药物设计开发领域,5-HT2C受体抑制剂备受关注,本文用比较分子相似性指数分析法(CoMSlA),研究34个二苯基取代吡咯烷酮类化合物的三维定量构效关系.考察衰减因子、电荷计算法以及不同作用场对构建模型的影响.建立的最佳模型交叉验证相关系数(q2)为0.571,非交叉验证相关系数(R2)为0.929,模型的标准偏差为0.225.发现疏水性在该类化合物与受体相互作用中发挥至关重要的作用,为进一步修饰结构提供指导.     

CoMFA analysis on a set of new noncompetitive GABAA receptor antagonists： fipronil and related analogs

Fipronil and related analogs, a set of new noncompetitive GABAA receptor antagonists, were investigated using comparative molecular field analysis （CoMFA） to explore their three-dimensional quantitative structure-activity relationships （3D-QSAR）. Considering the structural complexity of molecules of fipronil and related analogs, three different alignments were performed in this paper. CoMFA model for housefly receptor yield the leave-one-out and cross-validated correlation coefficient q^2 value of 0.511 and the conventional correlation coefficient r^2 value of 0.997. The new compounds with higher activity would be designed from this model. CoMFA model for rat receptor was not successful using all these three alignments, the reason of which maybe that some molecules adopt different conformations for rat receptor.     

两类促肾上腺皮质释放因子(CRF)抑制剂的CoMFA研究

Fipronil and related analogs, a set of new noncompetitive GABAA receptor antagonists, were investigated using comparative molecular field analysis (CoMFA) to explore their three-dimensional quantitative structure-activity relationships (3D-QSAR).Considering the structural complexity of molecules of fipronil and related analogs, three different alignments were performed in this paper. CoMFA model for housefly receptor yield the leave-one-out and cross-validated correlation coefficient q2 value of 0.511 and the conventional correlation coefficient r2 value of 0.997. The new compounds with higher activity would be designed from this model.CoMFA model for rat receptor was not successful using all these three alignments, the reason of which maybe that some molecules adopt different conformations for rat receptor.     

3D-QSAR and molecular docking studies of 1,3,5-triazene-2,4-diamine derivatives against r-RNA: novel bacterial translation inhibitors

Aminoglycoside mimetics inhibit bacterial translation by interfering with the ribosomal decoding site. To elucidate the structural properties of these compounds important for antibacterial activity, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to a set of 56 aminoglycosides mimetics. The successful CoMFA model yielded the leave-one-out (LOO) cross-validated correlation coefficient (q(2)) of 0.708 and a non-cross-validated correlation coefficient (r(2)) of 0.967. CoMSIA model gave q(2)=0.556 and r(2)=0.935. The CoMFA and CoMSIA models were validated with 36 test set compounds and showed a good r(pred)(2) of 0.624 and 0.640, respectively. Contour maps of the two QSAR approaches show that electronic effects dominantly determine the binding affinities. These obtained results were agreed well with the experimental observations and docking studies. The results not only lead to a better understanding of structural requirements of bacterial translation inhibitors but also can help in the design of novel bacterial translation inhibitors.     

Insight into the structural requirements of proton pump inhibitors based on CoMFA and CoMSIA studies

In the present study, a series of 179 quinoline and quinazoline heterocyclic analogues exhibiting inhibitory activity against Gastric (H+/K+)-ATPase were investigated using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods. Both the models exhibited good correlation between the calculated 3D-QSAR fields and the observed biological activity for the respective training set compounds. The most optimal CoMFA and CoMSIA models yielded significant leave-one-out cross-validation coefficient, q(2) of 0.777, 0.744 and conventional cross-validation coefficient, r(2) of 0.927, 0.914 respectively. The predictive ability of generated models was tested on a set of 52 compounds having broad range of activity. CoMFA and CoMSIA yielded predicted activities for test set compounds with r(pred)(2) of 0.893 and 0.917 respectively. These validation tests not only revealed the robustness of the models but also demonstrated that for our models r(pred)(2) based on the mean activity of test set compounds can accurately estimate external predictivity. The factors affecting activity were analyzed carefully according to standard coefficient contour maps of steric, electrostatic, hydrophobic, acceptor and donor fields derived from the CoMFA and CoMSIA. These contour plots identified several key features which explain the wide range of activities. The results obtained from models offer important structural insight into designing novel peptic-ulcer inhibitors prior to their synthesis.     

Three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of choline acetyltransferase inhibitors

As a basis for predicting structural features that may lead to the design of more potent and selective inhibitors of choline acetyltransferase (ChAT), the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out on a series of trans-1-methyl-4-(1-naphthylvinyl)pyridinium (MNVP+) analogs, which are known ChAT inhibitors. 3D-QSAR studies were carried out using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Since these inhibitors have extremely shallow potential energy minimum energy wells and low barriers to rotation, two dihedral angles unique to these inhibitors were systematically modified to reflect the energetically preferred conformations as determined by force field calculations. An optimum alignment rule was devised based on the conformations obtained from the molecular mechanics studies, using a common substructure alignment method. The studies involve a set of 21 compounds and experimentally determined molar IC50 values were used as the dependent variable in the analysis. The 3D-QSAR models have conventional r2-values of 0.953 and 0.954 for CoMFA and CoMSIA, respectively; similarly, cross-validated coefficient q2-values of 0.755 and 0.834 for CoMFA and CoMSIA, respectively, were obtained. On the basis of these predictive r2-values the model was tested using previously determined IC50 values. CoMSIA 3D-QSAR yielded better results than CoMFA.     

Receptor-based QSAR studies of non-peptide human oxytocin receptor antagonists

In the present study, QSAR calculations were performed on the receptor-based alignment of 58 non-peptide human oxytocin receptor antagonists. With the aid of different scoring functions (AutoDock 3.05 built-in and X-Score 1.2) the evolved receptor-ligand complexes were characterized. By means of various datasets it was confirmed that the scoring functions were not capable to predict the biological activity correctly in compounds containing a rigid derivative in the variable region. To improve the pKi prediction 3D-QSAR calculation was performed. The regions related to the biological activity were determined by using cross-validated r2(q2)-guided region selection (q2-GRS) method. The predictive power of the CoMFA model [r(pred)2=0.89, q2(LMO, five groups)=0.695+/-0.034] allowed prediction of the biological activities of newly synthesized compounds and confirmed the receptor-based alignment.     

地棘蛙素及其相关化合物对(α4)2(β2)3型烟碱乙酰胆碱受体的3D-QSAR研究

采用比较分子场分析法CoMFA研究地棘蛙素及其相关化合物的结构与活性关系,构建了三维构效关系模型,其相关参数q2(交叉验证相关系数)=0.526,r2(非交叉验证相关系数)=0.868,说明此模型具有良好的拟合能力和预报能力。依据模型,设计了8个地棘蛙素的类似物,并定量给出其预测活性值,证明模型可为设计高活性的烟碱乙酰胆碱受体激动剂提供理论依据。