A selectivity study of benzenesulfonamide derivatives on human carbonic anhydrase II/IX by 3D-QSAR,Molecular Docking and Molecular Dynamics Simulation

Nowadays, different approaches have been pursued with the intent to develop sulfonamide-like carbonic anhydrase inhibitors that possess better selectivity profiles toward the different human isoforms of the enzyme. Here, we used conventional 3D-QSAR methods, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA, to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models for benzenesulfonamide derivatives as human carbonic anhydrase (hCA) II/IX inhibitors. The theoretical models had good reliability (R²>0.75) and predictability (Q²>0.55), and the contour maps could graphically present the contributions of the force fields for activity and identify the structural divergence between human carbonic anhydrase II inhibitors and human carbonic anhydrase IX inhibitors. Consequently, we explored the selectivity of inhibitor for human carbonic anhydrase II and IX through molecular docking, and the difference of activity coincides with the potential binding mode well. According to the results of the predicted values and the molecule docking, we found that the inhibitors published in the literature had stronger inhibition on the hCA IX; based on the theoretical models, we designed seven new compounds with good potential activity and reasonably good ADMET profile, which could selectively inhibit hCA IX. Molecular Dynamics Simulation showed that newly-designed compound D7 had good selectivity on hCA IX. The findings from 3D-QSAR and docking studies maybe helpful in the rational drug design of isoform-selective inhibitors.     

类吗啡类拮抗物的结构与抑食活性的3D-QSAR研究

用比较力场分析研究了3,4-二甲基-4-(3-羟基苯基)哌啶及其衍生物类吗啡拮抗物的结构与抑食活性的关系,考察了网格结构和探针原子的影响.结果表明,立体效应和静电作用场是描述其抑食活性和进行结构性能关系研究的最重要的结构参数.     

A QSAR of the toxicity of amino-benzenes and their structures

The quantum chemical parameters and the topological indices have been calculated for the prediction of the toxicity of amino-benzenes in the environment, and work has been done on the multiple regression and neural networks. The combination of CoMFA with formation heat yields greatly improved results. A good model has been obtained which provides a basis for the studies of the toxic action mechanism.     

N-硝基脲类化合物除草活性的3D-QSAR研究

经活性测试,N-硝基脲类化合物对反枝苋(A. retroflexus L)和苏丹草(S. sudanenses)呈现除草活性。为进一步设计高活性的目标化合物,采用比较分子力场(CoMFA)对38个N-硝基脲类化合物进行三维定量构效关系(3D-QSAR)分析,建立了相关性显著、预测能力强的3D-QSAR模型(反枝苋：q2=0.674, r2=1.000, R2pred=0.9989,苏丹草：q2=0.635, r2=1.000, R2pred=0.9958)。根据CoMFA模型的立体场和静电场三维等势线图,在N’-苯环2, 5位引入体积大的正电荷取代基;3位引入负电荷基团;4, 6位引入体积大的负电荷基团有利于提高目标化合物对双子叶杂草反枝苋的除草活性,而在2位引入体积大的负电荷基团;3位引入体积小的负电荷基团;4位引入体积大的正电荷基团;5位引入体积大的取代基有利于提高目标化合物对单子叶杂草苏丹草的除草活性。     

3D-QSAR Study on Apicidin Inhibit Histone Deacetylase

For Histone Deacetylase (HDAC) Inhibitor, four 3D-QSAR models for four types of different activities, were constructed.The cross-valldated q^2 value of CoMFA Model 1 is 0.624 and the noncross-validated r2 value is 0.939. The cross-validated q^2 value of Model 2 for training set is 0.652 and the noncross-validated r^2 value is 0.963. The cross-validated q^2 value for Model 3 is 0.713, with noncross-validated r^2 value 0.947. The crossvalidated q2 value for Model 4 is 0.566 with noncross-validated r^2 value 0.959. Their predicted abilities were validated by different test sets which did not include in training set. Then the relationship between substituents and activities was analyzed by using these models and the main influence elements in different positions (positions 8 and 14) were found. The polar donor electron group of position 8 could increase the activity of inhibition of HDAC, because it could form chelation with the catalytic Zn. Suitable bulk and positive groups at position 14 are favorable to anti-HDAC activity. These models could web interpret the relationship between inhibition activity and apicidin structure affording us important information for structurebased drug design.     

CBP/P300溴结构域联芳基类抑制剂三维定量构效关系研究

CREB结合蛋白(CBP)和与其高度同源的P300蛋白是组蛋白乙酰化酶的两个亚型,两者通过它们的溴结构域(bromodomain,BRD)与染色质结合,目前,CBP/P300已经成为人类在肿瘤靶点领域中的研究热点。本研究基于CBP/P300溴结构域联芳基类抑制剂建立三维定量构效关系,采用比较分子力场分析法(Co MFA)和比较分子相似性指数分析法(Co MSIA)分别建立35个已知活性抑制剂的3D-QSAR模型,以确定CBP/P300溴结构域联芳基类抑制剂分子结构与生物活性之间的定量关系。Co MFA和Co MSIA模型活性数据p IC50的预测值与实验值基本一致,说明这两个模型具有较高的预测能力和统计学意义。根据Co MFA和Co MSIA模型所提供的立体场、静电场、疏水场、氢键给体场、氢键供体场等信息提出了改善此类抑制剂活性的药物设计思路,为指导设计具有更高活性的新分子和预测更加有效的CBP/P300溴结构域抑制剂提供理论依据。     

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。     

楝酰胺(Rocaglamide)类化合物的三维定量构效关系

采用比较分子力场分析(CoMFA)和比较分子相似因子分析(CoMSIA)方法,对训练集中的26个楝酰胺(Rocaglamide)类化合物进行了三维定量构效关系(3D-QSAR)研究,最终建立的CoMFA模型和CoMSlA模型的q<'2>分别为0.593和0.656.并对测试集中的5个化合物的生物活性进行了预测,结果表明...