咪唑并吡啶类化合物结构及PDE抑制活性的三维构效关系研究

对咪唑并吡啶类化合物作为环核苷酸磷酸二酯酶(PDE)的抑制剂的抑制活性进行了比较分子力场分析.结果表明,立体效应和静电作用场是描述对PDE抑制活性和进行结构性能关系研究的最重要的结构参数,提出了对该类化合物进行结构修饰的方法,并由新建立的三维定量构效关系模型对该类化合物的PDE抑制活性进行了预报.     

CoMFA and CoMSIA 3D-quantitative structure-activity relationship model on benzodiazepine derivatives, inhibitors of phosphodiesterase IV

Recently, we reported structurally novel PDE4 inhibitors based on 1,4-benzodiazepine derivatives. The main interest in developing bezodiazepine-based PDE4 inhibitors is in their lack of adverse effects of emesis with respect to rolipram-like compounds. A large effort has thus been made toward the structural optimization of this series. In the absence of structural information on the inhibitor binding mode into the PDE4 active site, 2D-QSAR (H-QSAR) and two 3D-QSAR (CoMFA and CoMSIA) methods were applied to improve our understanding of the molecular mechanism controlling the PDE4 affinity of the benzodiazepine derivatives. As expected, the CoMSIA 3D contour maps have provided more information on the benzodiazepine interaction mode with the PDE4 active site whereas CoMFA has built the best tool for activity prediction. The 2D pharmacophoric model derived from CoMSIA fields is consistent with the crystal structure of the PDE4 active site reported recently. The combination of the 2D and 3D-QSAR models was used not only to predict new compounds from the structural optimization process, but also to screen a large library of bezodiazepine derivatives.     

Three-dimensional quantitative structure--property relationship (3D-QSPR) models for prediction of thermodynamic properties of polychlorinated biphenyls (PCBs): enthalpy of sublimation

Three-dimensional quantitative structure--property relationship (3D-QSPR) models have been constructed using comparative molecular field analysis (CoMFA) to correlate the sublimation enthalpies at 298.15 K of a series of polychlorinated biphenyls (PCBs) with their CoMFA-calculated physicochemical properties. Various alignment schemes, such as atom fit, as is, and inertial were employed in this study. Separate CoMFA models were developed using different partial charge formalisms, namely, electrostatic potential (ESP) and Gasteiger-Marsili (GM) charges. Among the four different CoMFA models constructed for sublimation enthalpy (Delta(sub)H(m)(298.15 K)), the model that combined atom fit alignment and ESP charges yielded the greatest self-consistency (r(2) = 0.976) and internal predictive ability (r(cv)(2) = 0.750). This CoMFA model was used to predict Delta(sub)H(m)(298.15 K) of PCBs for which the corresponding experimental values are unavailable in the literature.     

Insight into the structural requirements of pyrimidine-based phosphodiesterase 10A (PDE10A) inhibitors by multiple validated 3D QSAR approaches

Schizophrenia is a complex disorder of thinking and behaviour (0.3?0.7% of the population is affected). The over-expression of phosphodiesterase 10A (PDE10A) enzyme may be a potential target for schizophrenia and Huntington’s disease. Because 3D QSAR analysis is one of the most frequently used modelling techniques, in the present study, five different 3D QSAR tools, namely CoMFA, CoMSIA, kNN-MFA, Open3DQSAR and topomer CoMFA methods, were used on a dataset of pyrimidine-based PDE10A inhibitors. All developed models were validated internally and externally. The non-commercial Open3DQSAR produced the best statistical results amongst 3D QSAR tools. The structural interpretations obtained from different methods were thoroughly analysed and were justified on the basis of information obtained from the crystal structure. Information from one method was mostly validated by the results of other methods and vice versa. In the current work, the use of multiple tools in the same analysis revealed more complete information about the structural requirements of these compounds. On the basis of the observations of the 3D QSAR studies, 12 new compounds were designed for better PDE10A inhibitory activity. The current investigation may help in further designing new PDE10A inhibitors with promising activity.     

Combined 2D and 3D-QSAR,molecular modelling and docking studies of pyrazolodiazepinones as novel phosphodiesterase 2 inhibitors

Selective inhibition of phosphodiesterase 2 (PDE2) in cells where it is located elevates cyclic guanosine monophosphate (cGMP) and acts as novel analgesic with antinociceptive activity. Three-dimensional quantitative structure–activity relationship (QSAR) studies for pyrazolodiazepinone inhibitors exhibiting PDE2 inhibition were performed using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and Topomer CoMFA, and two-dimensional QSAR study was performed using a Hologram QSAR (HQSAR) method. QSAR models were generated using training set of 23 compounds and were validated using test set of nine compounds. The optimum partial least squares (PLS) for CoMFA-Focusing, CoMSIA-SDH, Topomer CoMFA and HQSAR models exhibited good ‘leave-one-out’ cross validated correlation coefficient (q²) of 0.790, 0.769, 0.840 and 0.787, coefficient of determination (r²) of 0.999, 0.964, 0.979 and 0.980, and high predictive power (r²_pred) of 0.796, 0.833, 0.820 and 0.803 respectively. Docking studies revealed that those inhibitors able to bind to amino acid Gln859 by cGMP binding orientation called ‘glutamine-switch’, and also bind to the hydrophobic clamp of PDE2 isoform, could possess high selectivity for PDE2. From the results of all the studies, structure–activity relationships and structural requirements for binding to active site of PDE2 were established which provide useful guidance for the design and future synthesis of potent PDE2 inhibitors.     

3D-QSAR Study on Diindolylmethane and Its Analogues with Comparative Molecular Field Analysis (CoMFA)

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Three-dimensional quantitative structure-property relationship (3D-QSPR) models for prediction of thermodynamic properties of polychlorinated biphenyls (PCBs): enthalpy of vaporization

Three-dimensional Quantitative Structure-Property Relationship (QSPR) models have been derived using Comparative Molecular Field Analysis (CoMFA) to correlate the vaporization enthalpies of a representative set of polychlorinated biphenyls (PCBs) at 298.15 K with their CoMFA-calculated physicochemical properties. Various alignment schemes, such as inertial, as is, and atom fit, were employed in this study. The CoMFA models were also developed using different partial charge formalisms, namely, electrostatic potential (ESP) charges and Gasteiger-Marsili (GM) charges. The most predictive model for vaporization enthalpy (Delta(vap)H(m)(298.15 K)), with atom fit alignment and Gasteiger-Marsili charges, yielded r2 values 0.852 (cross-validated) and 0.996 (conventional). The vaporization enthalpies of PCBs increased with the number of chlorine atoms and were found to be larger for the meta- and para-substituted isomers. This model was used to predict Delta(vap)H(m)(298.15 K) of the entire set of 209 PCB congeners.     

Three-dimensional quantitative structure activity relationship (QSAR) of cytotoxic active 3,5-diaryl-4,5-dihydropyrazole analogs: a comparative molecular field analysis (CoMFA) revisited study

ABSTRACT: In vitro antitumor evaluation of the synthesized 46 compounds of 3,5-diaryl-4,5-dihydropyrazoles against EAC cell lines and 3D QSAR study using pharmacophore and Comparative Molecular Field Analysis (CoMFA) methods were described. CoMFA derived QSAR model shows a good conventional squared correlation coefficient r2 and cross validated correlation coefficient r2 cv 0.896 and 0.568 respectively. In this analysis steric and electrostatic field contribute to the QSAR equation by 70% and 30% respectively, suggesting that variation in biological activity of the compounds is dominated by differences in steric (van der Waals) interactions. To visualize the CoMFA steric and electrostatic field from partial least squares (PLS) analysis, contour maps are plotted as percentage contribution to the QSAR equation and are associated with the differences in biological activity. BACKGROUND: Pyrazole derivatives exhibit a wide range of biological properties including promising antitumor activity. Furthermore, Aldol condensation assisted organic synthesis has delivered rapid routes to N-containing heterocycles, including pyrazoles. Combining these features, the use of chalconisation-assisted processes will provide rapid access to a targeted dihydropyrazoles library bearing a hydrazino 3D QSAR study using pharmacophore and Comparative Molecular Field Analysis (CoMFA) methods were described for evaluation of antioxidant properties. RESULTS: Chalcones promoted 1 of the 2 steps in a rapid, convergent synthesis of a small library of hydrazinyl pyrazole derivatives, all of which exhibited significant antitumor activity against Ehrlich Ascites Carcinoma (EAC) human tumor cell line comparable to that of the natural anticancer doxorubicin, as a reference standard during this study. In order to understand the observed pharmacological properties, quantitative structure-activity relationship (3D QSAR) study was initiated. CONCLUSIONS: Chalcones heating provides a rapid and expedient route to a series of pyrazoles to investigate their chracterization scavenging properties. Given their favorable properties, in comparison with known anticancer, these pyrazole derivatives are promising leads for further development and optimization.     

磷酸二酯酶4b抑制剂定量构效关系及分子对接研究

磷酸二酯酶4(PDE4)是第二信使环磷酸腺苷(cAMP)选择性高亲和力的水解酶,影响气道平滑肌、炎性细胞和免疫细胞的功能,选择性PDE4b抑制剂作为抗炎药治疗哮喘和慢性阻塞性肺病(COPD)因为不会引起恶心呕吐等副反应而受到极大的关注。本文使用比较分子场(CoMFA)方法,对系列嘧啶二芳基取代的PDE4b抑制剂构建了合理的三维定量构效关系(3D-QSAR)模型,使用分子对接方法研究了抑制剂与酶的相互作用,发现该系列化合物的嘧啶环2位引入带有较大电负性基团取代的五元环状烃基可提升活性;嘧啶环4位、5位两个碳原子上建议保留小体积取代基;嘧啶环6位引入带有氢键给体或氢键受体取代的芳烃基可增加化合物活性。本研究可为后续合理设计高效的PDE4b抑制剂提供理论指导。     

二肽肽酶IV抑制剂的三维定量构效关系研究

二肽肽酶IV是一类用于治疗II型糖尿病具有潜在价值的关键酶, 很多此类酶的抑制剂用于处理此病具有相当好的有效性. 一系列N-取代的甘氨酰氰基吡咯烷衍生物对于二肽肽酶具有高的活性和选择性. 我们使用比较分子力场分析方法建立DPP-IV抑制剂——N-取代的甘氨酰氰基吡咯衍生物的三维定量构效关系, 该模型为设计用于治疗II型糖尿病的高效DPP-IV抑制剂提供结构信息. CoMFA模型的交叉验证相关系数q²＝0.575, 非交叉验证相关系数r²＝0.981, 绝对误差S＝0.184, F_9.68＝388.5. 使用七个预测集检验了模型的预测能力. 所得的模型解释了已有的构效关系, 并对同类化合物有较好的预测能力, 该模型可用于指导新型的DPP-IV抑制剂的设计与优化.     

四烃硫基四硫富瓦烯的电化学性质及三维定量结构性能关系研究

以四烃硫基四硫富瓦烯(TTF)为研究对象,合成了6个新的π电子给体化合物,并用循环伏安法考察了其电化学性质,同时用比较分子力场(CoMFA)研究了TTF衍生物的结构与其电化学性质的三维定量结构性能关系,提出了对TTF结构改造的方法,对新型TTF类化合物的合成有重要的指导意义.     

3D－QSAR Study on Diindolylmethane and Its Analogues with Comparative Molecular Field Analysis(CoMFA)

Comparative molecular field analysis (CoMFA),a three dimensional quantitative structure-activity relationship (3D-QSAR) method was applied to a series of diindolylmethane(DIM) analogs to study the relationship between their structure and their induction of CYP 1A1-associated ethoxyresorufin-O-deethylase(EROD) activity.A DISCO model of pharmacophore was derved to guide the superposition of the compounds.The coefficient of cross-validation (q^2) and non cross-validation(r^2) for the model established by the study are 0.827 and 0.988 respectively,the value of variance ratio (F) is 103.53 and standard error estimate (SEE)is 0.044.These values indicate that the CoMFA model derived is significant and might have a good prediction for the catalytic activity of DIM compounds.As a consequence,the predicted activity values of new designed compounds were all higher than that of the reported value.     

3D-QSAR Analysis of Naphthyltriazole(Lesinurad) Analogs as Potent Inhibitors of Urate Transporter 1

To obtain useful information for identifying inhibitors of urate transporter 1(URAT1), three-dimensional quantitative structure-activity relationship(3 D-QSAR) analysis was conducted for a series of lesinurad analogs via Topomer comparative molecular field analysis(CoMFA). A 3 D-QSAR model was established using a training set of 51 compounds and externally validated with a test set of 17 compounds. The Topomer CoMFA model obtained(q^2 = 0.976, r2 = 0.990) was robust and satisfactory. Subsequently, seven compounds with significant URAT1 inhibitory activity were designed according to the contour maps produced by the Topomer CoMFA model.     

Comparative molecular field analysis (CoMFA) model using a large diverse set of natural, synthetic and environmental chemicals for binding to the androgen receptor

A large number of natural, synthetic and environmental chemicals are capable of disrupting the endocrine systems of experimental animals, wildlife and humans. These so-called endocrine disrupting chemicals (EDCs), some mimic the functions of the endogenous androgens, have become a concern to the public health. Androgens play an important role in many physiological processes, including the development and maintenance of male sexual characteristics. A common mechanism for androgen to produce both normal and adverse effects is binding to the androgen receptor (AR). In this study, we used Comparative Molecular Field Analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3D-QSAR) technique, to examine AR-ligand binding affinities. A CoMFA model with r2 = 0.902 and q2 = 0.571 was developed using a large training data set containing 146 structurally diverse natural, synthetic, and environmental chemicals with a 10(6)-fold range of relative binding affinity (RBA). By comparing the binding characteristics derived from the CoMFA contour map with these observed in a human AR crystal structure, we found that the steric and electrostatic properties encoded in this training data set are necessary and sufficient to describe the RBA of AR ligands. Finally, the CoMFA model was challenged with an external test data set; the predicted results were close to the actual values with average difference of 0.637 logRBA. This study demonstrates the utility of this CoMFA model for real-world use in predicting the AR binding affinities of structurally diverse chemicals over a wide RBA range.     

哥纳三醇类似物抗A2780肿瘤细胞活性及三维定量构效关系研究

以合成的54个哥纳三醇类似物为研究对象, 测试了其体外抑制肿瘤A2780细胞株的活性, 对其中的37个化合物用比较分子力场(CoMFA)研究了哥纳三醇类似物结构与抑制A2780肿瘤细胞活性的三维定量构效关系, 提出了对哥纳香醇甲结构改造的方法, 对寻找更好活性的化合物有重要的指导意义     

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a series of thiazolone derivatives as novel inhibitors bound to the allosteric site of hepatitis C virus (HCV) NS5B polymerase were developed based on CoMFA and CoMSIA analyses. Two different conformations of the template molecule and the combinations of different CoMSIA field/fields were considered to build predictive CoMFA and CoMSIA models. The CoMFA and CoMSIA models with best predictive ability were obtained by the use of the template conformation from X-ray crystal structures. The best CoMFA and CoMSIA models gave q (2) values of 0.621 and 0.685, and r (2) values of 0.950 and 0.940, respectively for the 51 compounds in the training set. The predictive ability of the two models was also validated by using a test set of 16 compounds which gave r (pred) (2) values of 0.685 and 0.822, respectively. The information obtained from the CoMFA and CoMSIA 3D contour maps enables the interpretation of their structure-activity relationship and was also used to the design of several new inhibitors with improved activity.     

2-嘧啶氧基-N-芳基苄胺类化合物的ALS抑制活性的QSAR研究

乙酰乳酸合成酶(ALS)或乙酰羟酸合成酶(AHAS)存在于植物的生长过程中, 很多此类酶的抑制剂实际上作为除草剂被广泛用于农业生产中. 生物活性测试结果表明, 2-嘧啶氧基-N-芳基苄胺类化合物对ALS具有一定的抑制活性. 在此基础上, 我们用两种三维定量构效关系(3D-QSAR)研究方法: 比较分子立场分析(CoMFA)和比较分子相似性指数分析(CoMSIA), 对该类化合物进行了3D-QSAR研究, 并建立了相关的预测模型. 其中, CoMFA模型的交叉验证相关系数(r_cv²)为0.801, 非交叉验证相关系数(r²)为0.947, 标准偏差(s)为0.136, F值为133.371. CoMSIA模型的r_cv²为0.744, r²为0.883, s为0.202, F值为56.472. 计算结果表明, 2-嘧啶氧基-N-芳基苄胺类化合物与ALS抑制活性有一定的相关性. 获得的CoMFA和CoMSIA模型, 将应用于指导该类化合物的设计.     

A ligand-based comparative molecular field analysis (CoMFA) and homology model based molecular docking studies on 3′, 4′-dihydroxyflavones as rat 5-lipoxygenase inhibitors: Design of new inhibitors

In this study, ligand based comparative molecular field analysis (CoMFA) with five principal components was performed on class of 3′, 4′-dihydroxyflavone derivatives for potent rat 5-LOX inhibitors. The percentage contributions in building of CoMFA model were 91.36% for steric field and 8.6% for electrostatic field. R² values for training and test sets were found to be 0.9320 and 0.8259, respectively. In case of LOO, LTO and LMO cross validation test, q² values were 0.6587, 0.6479 and 0.5547, respectively. These results indicate that the model has high statistical reliability and good predictive power. The extracted contour maps were used to identify the important regions where the modification was necessary to design a new molecule with improved activity. The study has developed a homology model for rat 5-LOX and recognized the key residues at the binding site. Docking of most active molecule to the binding site of 5-LOX confirmed the stability and rationality of CoMFA model. Based on molecular docking results and CoMFA contour plots, new inhibitors with higher activity with respect to the most active compound in data set were designed.     

Comparative molecular field analysis (CoMFA) of new herbicidal sulfonylurea compounds

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嘧啶（氧）苯甲酸类除草剂的3D—QSAR研究

利用比较分子场分析 (Co MFA)方法 ,对 2 0种嘧啶 (氧 )苯甲酸类化合物进行了三维定量构效关系(3 D-QSAR)研究。得到了具有较强预测能力的 QSAR模型。并对此模型进行了验证 ,在此基础上 ,设计了具有更高活性的化合物。