基于启发式变量筛选方法研究与雌激素β受体结合的化合物结构与活性之间的关系

雌激素类化合物由于其对人和野生动物健康的负面影响而受到广泛关注.雌激素受体存在两种亚型(ERα和ERβ),化合物与两种受体亚型在结合活性和化合物结构特征方面存在差异.以31种与雌激素β受体亚型(ERβ)结合的化合物为研究对象,采用启发式变量筛选方法,从1524个变量中筛选出5个与化合物活性(lgRBA)最相关的变量,然后采用多元线性回归(MLR)建立最佳预测模型.模型相关性显著,而且具有良好的稳健性和预测能力(r2=0.829,q2LOO=0.742,r2pred=0.772,q2ext=0.724,RMSEE=0.395).同时揭示了影响化合物与ERβ受体结合的配体化合物分子的结构特征,并对模型的应用域进行了研究.     

甲状腺激素受体配体化合物的定量构效关系(QSAR)研究

研究了68个TR（Thyroid Hormone Receptor,甲状腺激素受体）配体化合物的化学结构与活性的定量构效关系．采用实验室新近提出的三维原子场全息相互作用矢量,对化合物进行了结构参数化表达,采用逐步回归对变量进行筛选后,建立了定量构效关系模型．复相关系数和交互检验复相关系数R^2=0．767,Q^2=0．625（TRα）,R^2=0．734,Q^2=0．61（TRβ）．模型具有良好的稳定性和预测能力,证明了该三维原子场全息相互作用矢量在分子结构表征和生物活性预测上的适用性,并可应用于潜在和新型的TR配体化合物的设计和开发．     

7-羟基异黄酮及其衍生物的合成与选择性雌激素受体结合的构效关系研究

以多酚类化合物和多取代苯乙酸类化合物为原料,用一锅法合成了24个7-羟基异黄酮类化合物;并从一锅法制得的3d,3g经脱除甲基得到两个2'-羟基取代的异黄酮化合物4a和4b.雌激素受体(Estrogen receptors,ERs)的选择性结合活性试验表明:26个化合物(包括4个新化合物3r,3s,3u和3v)中,9个化合物与ERβ相对于ERα的选择性作用强于染料木素(Genistein);发现7,8-二羟基异黄酮类化合物与ERβ相对结合能力高于相应7-羟基异黄酮类化合物;4'取代基对化合物与ERβ结合相对于ERα的选择性影响从大到小为:H>Cl>F>OH;2',3'及5'位取代基降低异黄酮对ERα和ERβ的亲和性.     

雌激素β受体喹啉类配体的分子对接及3D-QSAR研究

对33个喹啉衍生物的雌激素β受体活性进行了分子对接以及比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA). 对接结果显示氢键和疏水作用是配体与受体结合的主要因素,同时结果亦显示对接结合能与观测值pIC50具有极显著的线性相关性. 根据对接后各优势构象将33个样本进行叠合并进行CoMFA与CoMSIA研究,均得到了较优的结果,其中以选用立体场、静电场和疏水场建立的CoMSIA模型结果最优,其主成分数,r2,q2（LOO）和r2pred分别为2, 0.894, 0.708和0.802. 构效关系模型分析显示基团的空间位阻、电性及疏水作用是影响活性的主要因素     

基于纳米结构双层类脂膜的雌激素传感器

采用铂盘电极支撑的纳米金修饰的双层类脂膜(Pt/BLM/Au)来固定雌激素受体(ER),制备Pt/BLM/Au/ER用于检测雌激素的传感器.电极不同修饰状态分别用循环伏安法和交流阻抗法进行表征.以交流阻抗法测得电极结合雌激素后阻抗的改变与17β-雌二醇(E2)的浓度在5～150 ng/L范围呈良好线性关系,相关系数r=...     

基于糖皮质激素受体调节剂波尼松龙的定量构效关系研究

为了探讨糖皮质激素受体调节剂波尼松龙系列的结构和活性之间的关系,首次使用比较分子力场(CoMFA)和比较分子相似性指数分析(CoMSIA)方法对77个靶标分子建立三维定量构效关系(3D-QSAR)模型.在基于配体叠合的基础上,得到了最好的CoMSIA模型(Q2=0.504,R2ncv=0.849,SEE=0.283,F=56.365和R2pred=0.792).模型的三维等势线图分析说明了疏水性基团在R1取代基位置有利于提高活性,亲水性基团在R2取代基位置有利于提高活性.此外,分子对接分析结果显示了与波尼松龙形成一些氢键的氨基酸Asn564,Gln642,Thr739在糖皮质激素受体调节剂中有重要作用.本文得到的结果能够更好地帮助理解糖皮质激素受体调节剂作用机理,并为今后的药物设计与合成提供了新思路.     

两类HPPD酶抑制剂的比较分子场分析研究

用比较分子场分析法（CoMFA）研究了环已二酮类及3-烷基酸-2-环已烯酯类化 合物的结构与活性的关系。本研究从蛋白酶与底物动力学模拟的复合物结构出发构 建两类抑制剂化合物分子的构象，并进行了全空间搜索，CoMFA分析得到了较好的 模型（交叉验证回归系数q~2 = 0.779，模型的线性回归系数r~2 = 0.989）。该方 程不仅可以帮助推测抑制剂与受体的结合方式，还可定量地预测结构相近的类似物 活性，为设计合成新的HPPD酶抑制剂提供了理论依据。     

新型含吡啶酮（吡唑）结构的A2a/A2b双靶点腺苷受体拮抗剂的合成及生物活性研究

设计并合成了具有吡啶酮或吡唑结构的6个新型双靶点（A_2a和A_2b）腺苷受体拮抗剂。其结构经¹H NMR、¹³C NMR和HR-MS（ESI）表征。采用cAMP法评价了目标化合物（11a~11f）对A_2a和A_2b受体的抑制活性。活性测试结果表明：该系列化合物对A_2a和A_2b受体均有较好的抑制活性。其中化合物11e抑制活性最强,抑制A_2a和A_2b受体的IC₅₀值分别为8.188 nM和15.22 nM,11e对A_2bR受体的抑制活性优于阳性对照药AB928（IC₅₀=36.48 nM）。此外,利用分子对接研究了化合物11e与A_2a和A_2b靶点的结合情况,结果表明：化合物11e与A_2a和A_2b靶点具有较好的亲和作用。     

二氢异喹啉类BACE1抑制剂的特征结构及结合模式研究

β-分泌酶(BACE1)是水解淀粉样前体蛋白生成β-淀粉样多肽的关键限速酶,近年来已成为治疗阿尔茨海默症的一个理想靶点。本文以34个二氢异喹啉类BACE1抑制剂为研究对象,采用比较分子相似性指数(CoMSIA)法定量研究其结构与生物活性间的构效关系,并建立可靠的3D-QSAR预测模型,运用分子对接法分析其与受体BACE1间的结合模式。结果显示,基于立体场、疏水场和氢键供体场建立的CoMSIA模型稳定性良好、预测能力强(Q~2=0.47,R_(ncv)~2=0.93,R_(pre)~2=0.95)。本研究所得模型和信息较好地解释了二氢异喹啉类BACE1抑制剂的结构特征及其与受体间的结合模式,为后续新型BACE1抑制剂的设计开发提供理论指导。     

以S-中心Preyssler型多酸为模板构筑有机-无机杂化材料

采用水热合成方法构建了基于Preyssler型多酸[S5W30O110]的有机-无机杂化材料,其分子式为[HKS5W30O110]·（2,2-Hbpy）8·2H2O（1,bpy=bipyridine）.单晶X-射线衍射分析表明化合物1是由S-中心的Preyssler型多酸作为模版,被2,2-联吡啶分子包围形成的核壳结构的有机无机杂化材料.这是第一例基于S-中心Preyssler型多酸的超分子核壳结构.其中质子化的2,2’-联吡啶有机基团通过静电作用与Preyssler型多酸分子构筑成有机无机杂化材料.该化合物属于三斜晶系,空间群为P-1.晶胞参数：a=1.795 05（2）nm,b=1.834 78（2）nm,c=4.128 16（4）nm,α=85.061 0（10）°,β=80.616 0（10）°,γ=60.721 0（10）°,晶胞体积为11.700 2（2）nm3.     

3D-QSAR and docking studies of estrogen compounds based on estrogen receptor β

Close attention has been paid to estrogen compounds because these chemicals may pose a serious threat to the health of humans and wildlife. Estrogen receptor (ER) exists as two subtypes, ERα and ERβ. The difference in amino acids sequence of the binding sites of ERα and ERβ might lead to a result that some synthetic estrogens and naturally occurring steroidal ligands have different relative affinities and binding modes for ERα and ERβ. In this investigation, comparative molecular similarity indices analysis...     

Synthesis of 2-phenylbenzofuran derivatives and selective binding activities on estrogen receptor

An improved chemical reaction protocol with short time and easy work-up was described here for 2-phenylbenzofuran derivatives. The final purified products, 2-phenylbenzofuran derivatives 5a-g and the intermediate diols 4a-g, were evaluated for their estrogen receptor (ER) binding affinity and selective activity in vitro. Among these fourteen tested compounds, 4g and 5g showed higher binding affinity on ER subtypes, ERα and ERβ. Compound 4g exhibited preferable ERα binding, while 5g was more estrogen selective for ERβ. The molecular docking was also performed to explore the detailed interactive interface between ER and the compounds.     

3-氨磺酰苯甲酸类AKR1C3抑制剂的3D-QSAR和分子对接研究

醛酮还原酶1C3(AKR1C3)作为治疗前列腺癌的新靶点已成为研究热点,3-氨磺酰苯甲酸衍生物对其具有高效的选择性和抑制活性。本文采用比较分子场分析(COMFA)和比较分子相似性指数分析(COMSIA)方法,将经分子对接后的34个优势构象组成训练集和11个优势构象组成测试集,构建三维定量构效关系(3D-QSAR)模型。COMFA模型的交叉验证系数(q2),非交叉验证系数(R2),标准偏差(SEE)和F值分别为0.761,0.973,0.122,185.963;自举法回归系数为R2bs=0.98。最佳组合COMSIA模型的q2,R2,SEE,F和R2bs分别为0.734,0.984,0.097,147.850,0.994。COMFA和COMSIA模型的系统外部测试R2pred分别为0.864和0.756,r2m分别为0.8127和0.5377。这些结果表明,所建立的QSAR模型具有较高的可靠性和较强预测能力。经三维等势图分析可知,在2、5或6位适当增加取代基体积,或在5位引入氢键受体,或在7位引入负电性取代基则能提高化合物的生物活性。该模型为进一步设计具有更优选择性和活性的化合物提供了理论依据。     

Quantitative structure-activity relationships for a series of selective estrogen receptor-beta modulators

The estrogen receptor-beta subtype (ERβ) is an attractive drug target for the development of novel therapeutic agents for hormone replacement therapy. Hologram quantitative structure-activity relationships (HQSAR) were conducted on a series of 6-phenylnaphthalene and 2-phenylquinoline derivatives, employing values of ERβ binding affinity. A training set of 65 compounds served to derive the models. The best statistical HQSAR model (q ²?=?0.73 and r ²?=?0.91) was generated using atoms, bonds, connections and donor and acceptor as fragment distinction parameters, and fragment size default (4–7) with hologram length of 199. The model was used to predict the binding affinity of an external test set of 16 compounds, and the predicted values were in good agreement with the experimental results. The final HQSAR model and the information obtained from 2D contribution maps should be useful for the design of novel ERβ modulators having improved affinity.     

Effects of gamma irradiation on the DNA-protein complex between the estrogen response element and the estrogen receptor

Signaling by estrogens, risk factors in breast cancer, is mediated through their binding to the estrogen receptor protein (ER), followed by the formation of a complex between ER and a DNA sequence, called estrogen response element (ERE). Anti-estrogens act as competitive inhibitors by blocking the signal transduction. We have studied in vitro the radiosensitivity of the complex between ERα, a subtype of this receptor, and a DNA fragment bearing ERE, as well as the influence of an estrogen (estradiol) or an anti-estrogen (tamoxifen) on this radiosensitivity. We observe that the complex is destabilized upon irradiation with γ rays in aerated aqueous solution. The analysis of the decrease of binding abilities of the two partners shows that destabilization is mainly due to the damage to the protein. The destabilization is reduced when irradiating in presence of tamoxifen and is increased in presence of estradiol. These effects are due to opposite influences of the ligands on the loss of binding ability of ER. The mechanism that can account for our results is: binding of estradiol or tamoxifen induces distinct structural changes of the ER ligand-binding domain that can trigger (by allostery) distinct structural changes of the ER DNA-binding domains and thus, can differently affect ER-ERE interaction.     

Comparison of Estrogen Receptor α and β Subtypes Based on Comparative Molecular Field Analysis (CoMFA)

Abstract

A substantial body of evidence indicates that both humans and wildlife suffer adverse health effects from exposure to environmental chemicals that are capable of interacting with the endocrine system. The recent cloning of the estrogen receptor β subtype (ER-β) suggests that the selective effects of estrogenic compounds may arise in part by the control of different subsets of estrogen-responsive promoters by the two ER subtypes, ER-α and ER-β. In order to identify the structural prerequisites for ligand-ER binding and to discriminate ER-α and ER-3 in terms of their ligand-binding specificities, Comparative Molecular Field Analysis (CoMFA) was employed to construct a three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) model on a data set of 31 structurally-diverse compounds for which competitive binding affinities have been measured against both ER-α and ER-β. Structural alignment of the molecules in CoMFA was achieved by maximizing overlap of their steric and electrostatic fields using the Steric and Electrostatic ALignment (SEAL) algorithm. The final CoMFA models, generated by correlating the calculated 3D steric and electrostatic fields with the experimentally observed binding affinities using partial least-squares (PLS) regression, exhibited excellent self-consistency (r ² > 0.99) as well as high internal predictive ability (q ² > 0.65) based on cross-validation. CoMFA-predicted values of RBA for a test set of compounds outside of the training set were consistent with experimental observations. These CoMFA models can serve as guides for the rational design of ER ligands that possess preferential binding affinities for either ER-α or ER-β. These models can also prove useful in risk assessment programs to identify real or suspected EDCs.     

Synthesis of novel nitro-substituted triaryl pyrazole derivatives as potential estrogen receptor ligands

Novel tetrasubstituted pyrazole derivatives bearing a nitro substituent on their A-phenol ring were synthesized and their binding affinity towards the estrogen receptor (ER) subtypes ERalpha and ERbeta was determined. Among compounds tested, the 2-nitrophenol derivative 5c was found to bind satisfactorily to both estrogen receptor subtypes (RBAalpha=5.17 and RBAbeta=3.27). In general, the introduction of a nitro group into the A ring of these compounds was found to benefit their ERbeta binding abilities.     

A priming role of local estrogen on exogenous estrogen-mediated synaptic plasticity and neuroprotection

The localization of estrogen (E2) has been clearly shown in hippocampus, called local hippocampal E2. It enhanced neuronal synaptic plasticity and protected neuron form cerebral ischemia, similar to those effects of exogenous E2. However, the interactive function of hippocampal and exogenous E2 on synaptic plasticity activation and neuroprotection is still elusive. By using hippocampal H19-7 cells, we demonstrated the local hippocampal E2 that totally suppressed by aromatase inhibitor anastrozole. Anastrozole also suppressed estrogen receptor (ER)β, but not ERα, expression. Specific agonist of ERα (PPT) and ERβ (DPN) restored ERβ expression in anastrozole-treated cells. In combinatorial treatment with anastrozole and phosphoinositide kinase-3 (PI-3K) signaling inhibitor wortmannin, PPT could not improve hippocampal ERβ expression. On the other hand, DPN induced basal ERβ translocalization into nucleus of anastrozole-treated cells. Exogenous E2 increased synaptic plasticity markers expression in H19-7 cells. However, exogenous E2 could not enhance synaptic plasticity in anastrozoletreated group. Exogenous E2 also increased cell viability and B-cell lymphoma 2 (Bcl2) expression in H(2)O(2)-treated cells. In combined treatment of anastrozole and H(2)O(2), exogenous E2 failed to enhance cell viability and Bcl2 expression in hippocampal H19-7 cells. Our results provided the evidence of the priming role of local hippocampal E2 on exogenous E2-enhanced synaptic plasticity and viability of hippocampal neurons.