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Quantitative Structure-activity Relationships最新文献

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3D-Quantitative Structure Activity Relationships of Biphenyl Carboxylic Acid MMP-3 Inhibitors: Exploring Automated Docking as Alignment Method 联苯羧酸类MMP-3抑制剂的三维定量构效关系:探索自动对接定位方法
Pub Date : 2001-10-01 DOI: 10.1002/1521-3838(200110)20:3<215::AID-QSAR215>3.0.CO;2-9
I. Muegge, B. Podlogar
A series of CoMFA models have been derived from docking-based and atom-based alignments. The statistics of these approaches has been compared to determine whether a docking approach can be employed as an automated alignment tool for the development of 3D-QSAR models. Using a well-characterized training set of 51 biphenyl carboxylic acid MMP-3 inhibitors, the docking-based alignment provided by a DOCK4/PMF-scoring protocol has yielded statistically significant, cross-validated CoMFA models comparable to those derived with a traditional atom-based alignment technique. Field fit minimization has been applied to refine the atom-based and docking-based alignments. The refinement appears to be beneficial for the docking-based approach. For the atom-based alignment, however, field-fit refinement has not resulted in improved CoMFA models. The statistically best CoMFA model has been created by the atom-based alignment that has been found, however, to be inconsistent with the stromelysin crystal structure. The docking alignment refined by field-fit alignment has resulted in a final alignment that is consistent with the crystal structure and only slightly statistically inferior to the atom-based aligned CoMFA model. The results show␣the ability of an automated docking/field-fit alignment technique to provide self-consistent CoMFA alignments.
一系列的CoMFA模型已经从基于对接和基于原子的对准中衍生出来。对这些方法的统计数据进行了比较,以确定对接方法是否可以作为3D-QSAR模型开发的自动对准工具。使用具有良好特征的51个联苯羧酸MMP-3抑制剂的训练集,由DOCK4/ pmf评分协议提供的基于对接的比对得到了具有统计学意义的交叉验证CoMFA模型,可与传统的基于原子的比对技术相媲美。场拟合最小化已被应用于改进基于原子和基于对接的对准。这种改进似乎对基于对接的方法是有益的。然而,对于基于原子的对准,场拟合的细化并没有导致改进的CoMFA模型。统计上最好的CoMFA模型是由基于原子的排列创建的,然而,它与stromelysin晶体结构不一致。通过场拟合校准改进的对接校准导致最终的校准与晶体结构一致,在统计上仅略低于基于原子的校准CoMFA模型。结果显示,自动化对接/现场拟合对齐技术能够提供自一致的CoMFA对齐。
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引用次数: 17
Modeling the Relative Binding Affinity of Steroids to the Progesterone Receptor with Probabilistic Neural Networks 用概率神经网络模拟类固醇与黄体酮受体的相对结合亲和力
Pub Date : 2001-10-01 DOI: 10.1002/1521-3838(200110)20:3<223::AID-QSAR223>3.0.CO;2-D
Ş. Niculescu, K. Kaiser
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引用次数: 2
Use of Support Vector Machine in Pattern Classification: Application to QSAR Studies 支持向量机在模式分类中的应用:在QSAR研究中的应用
Pub Date : 2001-10-01 DOI: 10.1002/1521-3838(200110)20:3<227::AID-QSAR227>3.0.CO;2-Y
R. Czerminski, A. Yasri, D. Hartsough
The Support Vector Machine (SVM) approach for classification and regression problems was originally developed by Vapnik and co-workers [1]. For the last few years it has been gaining acceptance in the machine learning community [2]. The purpose of this paper is to evaluate SVM performance in the quantitative structure-activity relationship (QSAR) domain for classification applications and to compare the performance of one particular implementation of an SVM [3] to one particular implementation of an artificial neural network (ANN) [4]. For this purpose, we used artificial data simulating various response surfaces, and biological data derived from the literature covering various pharmacological domains. The results obtained on biological data are also compared to previous work using other modeling techniques. We also discuss the usage of SVM in building QSAR models for biological activity of drugs.
用于分类和回归问题的支持向量机(SVM)方法最初是由Vapnik及其同事开发的[1]。在过去的几年里,它已经在机器学习社区中获得了认可[2]。本文的目的是评估SVM在分类应用的定量结构-活动关系(QSAR)领域中的性能,并比较SVM的一种特定实现[3]与人工神经网络(ANN)的一种特定实现[4]的性能。为此,我们使用了模拟各种反应面的人工数据,以及从涵盖各种药理学领域的文献中获得的生物学数据。在生物数据上获得的结果也与以前使用其他建模技术的工作进行了比较。我们还讨论了SVM在构建药物生物活性QSAR模型中的应用。
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引用次数: 95
Three dimensional principal component analysis used for the study of enzyme kinetics. An empirical approximation for the determination of the dimensions of component matrices 用于酶动力学研究的三维主成分分析。测定成分矩阵的维数的经验近似
Pub Date : 2001-10-01 DOI: 10.1002/1521-3838(200110)20:3<241::AID-QSAR241>3.0.CO;2-D
H. Morais, C. Ramos, E. Forgács, A. Jakab, T. Cserháti, J. Oliviera, Tibor Illés, Z. Illés
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引用次数: 5
Human P‐Glycoprotein Pseudoreceptor Modeling: 3D‐QSAR Study on Thioxanthene Type Multidrug Resistance Modulators 人P糖蛋白假受体模型:硫代蒽型多药耐药调节剂的3D - QSAR研究
Pub Date : 2001-07-01 DOI: 10.1002/1521-3838(200107)20:2<130::AID-QSAR130>3.0.CO;2-6
I. Pajeva, M. Wiese
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引用次数: 10
CoMFA Study on Adenosine A2A Receptor Agonists 腺苷A2A受体激动剂的CoMFA研究
Pub Date : 2001-07-01 DOI: 10.1002/1521-3838(200107)20:2<124::AID-QSAR124>3.0.CO;2-V
I. Doytchinova, I. Valkova, R. Natcheva
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引用次数: 8
A Novel Chemogenomics Knowledge-Based Ligand Design Strategy—Application to G Protein-Coupled Receptors 一种新的基于化学基因组学知识的配体设计策略——在G蛋白偶联受体中的应用
Pub Date : 2001-07-01 DOI: 10.1002/1521-3838(200107)20:2<115::AID-QSAR115>3.0.CO;2-V
E. Jacoby
In the frame of the discussion of monoamine-related GPCRs, a novel knowledge-based ligand design strategy is presented. The strategy is founded on the integration of both, the deconvolution of known ligands into their component fragments and the structural bioinformatics comparison of the binding sites for the individual ligand fragments. Positioning analyses of monoamine-related GPCRs in 1) the sequence space of the seven transmembrane domains of the receptors, and 2) in the sequence spaces of the previously identified three distinct ligand fragment binding regions of the monoamine GPCRs, are carried out in the perspective to characterize orphan receptors and monoamine receptors for which no specific ligands are yet known. Compared to the commonly accepted strategy to analyze the overall sequence identity of the seven transmembrane domains in order to find starting points for lead finding and ligand design programs, the strategy to localize the sequence homology to the different ligand fragment binding sites clearly enhances the identification of putative similarities for the orphan receptors. Correspondingly, in the ligand space, by the analysis of both, the ligand architectures and the structures of the component “one-site filling” fragments of known GPCR ligands, it is then possible, by referring to the locally most directly related and characterized receptors, to identify those component ligand fragments which based on the binding site similarities are potentially best suited for the design of ligands tailored to the new target receptor. Predictions are made for several orphan GPCRs, including GPR7, GPR8, GPR14, GPR24, GPR57, GPR58 and AF021818, as well as for the 5HT1E and 5HT5 serotonin receptors for which no specific agonists and antagonists are yet known. Although the method is herein discussed with a focus on GPCRs, it is expected that such chemogenomics knowledge-based strategies – bridging the chem- and bioinformatics worlds – should open novel perspectives in drug discovery for orphan targets revealed by the human genome project belonging to other therapeutic target families.
在讨论单胺相关gpcr的框架下,提出了一种新的基于知识的配体设计策略。该策略建立在两者的整合上,已知配体的反卷积到它们的组成片段中,以及单个配体片段结合位点的结构生物信息学比较。对单胺相关gpcr进行定位分析,从1)受体的7个跨膜结构域的序列空间,以及2)先前鉴定的单胺相关gpcr的3个不同配体片段结合区域的序列空间进行定位分析,以表征孤儿受体和单胺受体,其中没有特定的配体已知。与通常通过分析7个跨膜结构域的整体序列同一性来寻找引子寻找和配体设计程序的起点的策略相比,将序列同源性定位到不同配体片段结合位点的策略明显增强了对孤儿受体的假定相似性的识别。相应地,在配体空间中,通过对已知GPCR配体的配体结构和组成部分“单位点填充”片段的结构进行分析,然后有可能通过参考局部最直接相关和表征的受体,确定基于结合位点相似性的那些组成配体片段可能最适合设计适合新靶受体的配体。预测了几种罕见的gpcr,包括GPR7、GPR8、GPR14、GPR24、GPR57、GPR58和AF021818,以及5HT1E和5HT5 5 -羟色胺受体,目前还没有特异性的激动剂和拮抗剂。虽然本文讨论的方法主要集中在gpcr上,但预计这种基于化学基因组学知识的策略-连接化学和生物信息学世界-应该为属于其他治疗靶点家族的人类基因组计划揭示的孤儿靶点的药物发现开辟新的视角。
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引用次数: 39
Identification of Novel Potent Inhibitors for ATP‐Phosphoribosyl Transferase Using Three‐Dimensional Structural Database Search Technique 利用三维结构数据库搜索技术鉴定ATP -磷酸核糖基转移酶的新型有效抑制剂
Pub Date : 2001-07-01 DOI: 10.1002/1521-3838(200107)20:2<143::AID-QSAR143>3.0.CO;2-R
K. Gohda, D. Ohta, A. Kozaki, K. Fujimori, I. Mori, T. Kikuchi
We identified new potent inhibitors for ATP-phosphoribosyl transferase, which is the first enzyme in histidine biosynthesis pathway, using three-dimensional database search (3D-search) technique. The 3D-search was based on the structure of product molecule, N-1-(5′-phosphoribosyl)-ATP, as a template to find molecules targeting to the binding sites of two substrates (ATP and 5′-phosphoribosyl-1-pyrophosphate), i.e., bi-substrate mimicking. Four commercially-available compounds with three different chemical classes were examined out of 36 low-molecular weight compounds selected from the hits of the searches. Amino-(chlorophenyl)-triazolopyrimidine compounds, which are the simplest and smallest ones, showed potent activity (e.g., 92% inhibition at 100 μM). The structural comparison with the product molecule suggests that the simultaneous occupation of two substrate-binding sites likely enhances the enzyme inhibition. The most potent compound examined in this study was a disulfide-bond containing molecule (IC50=50 nM), whose mode of action seems to be different from the others. Further studies using its derivatives were carried out for clarification.
利用三维数据库搜索(3D-search)技术,我们发现了组氨酸生物合成途径中第一个酶atp -磷酸核糖基转移酶的新有效抑制剂。3d搜索以产物分子N-1-(5′-磷酸核糖基)-ATP的结构为模板,寻找靶向两种底物(ATP和5′-磷酸核糖基-1-焦磷酸)结合位点的分子,即双底物模拟。从搜索结果中选择的36种低分子量化合物中,检测了具有三种不同化学类别的四种商业可用化合物。其中,最简单、最小的氨基(氯苯基)-三唑嘧啶类化合物在100 μM的抑制率为92%。与产物分子的结构比较表明,同时占据两个底物结合位点可能增强了酶的抑制作用。本研究中检测到的最有效的化合物是一种含二硫键的分子(IC50=50 nM),其作用方式似乎与其他化合物不同。利用其衍生物进行了进一步的研究以澄清。
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引用次数: 6
Theoretical Elucidation of Structure-Antioxidant Activity Relationships for Thiazolidinone Derivatives 噻唑烷酮衍生物结构-抗氧化活性关系的理论阐释
Pub Date : 2001-07-01 DOI: 10.1002/1521-3838(200107)20:2<139::AID-QSAR139>3.0.CO;2-7
You-min Sun, X. Wang, Hong-yu Zhang, Dezhan Chen
Thiazolidinone Derivatives (TD) are a novel class of calcium ion (Ca2+) antagonists possessing both Ca2+ overload inhibition and antioxidant activity. The free radical scavenging activity of TD play a key role in its cardioprotective processes. To elucidate the structure-antioxidant activity relationships (SAAR) for TD, a series of phenolic analogues of TD were constructed by adding various substituents to phenol step by step. And the theoretical parameter characterizing the free radical scavenging activity, O–H bond dissociation energy (BDE), was calculated for these phenols by quantum chemical method AM1/B3LYP/6-31G**. Thus, the contribution of each substituent to the O–H BDE was obtained. As a result, not only the SAAR for TD was explained, but also the understanding on TD's antioxidative mechanism was deepened.
噻唑烷酮衍生物(TD)是一类新型的钙离子(Ca2+)拮抗剂,具有Ca2+过载抑制和抗氧化活性。TD的自由基清除活性在其心脏保护过程中起关键作用。为了阐明TD的结构-抗氧化活性关系,通过在苯酚上逐级添加不同取代基,构建了一系列TD的酚类类似物。并利用量子化学方法AM1/B3LYP/6-31G**计算了表征这些酚类化合物清除自由基活性的理论参数O-H键离解能(BDE)。从而得到了每个取代基对O-H BDE的贡献。研究结果不仅解释了TD的SAAR,而且加深了对TD抗氧化机理的认识。
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引用次数: 8
O–H Bond Dissociation Energies of Phenolic Compounds are Determined by Field/Inductive Effect or Resonance Effect?A DFT Study and Its Implication 酚类化合物的O-H键离解能是由场/感应效应还是共振效应决定的?一项DFT研究及其意义
Pub Date : 2001-07-01 DOI: 10.1002/1521-3838(200107)20:2<148::AID-QSAR148>3.0.CO;2-7
Hong-yu Zhang, You-min Sun, Dezhan Chen
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引用次数: 49
期刊
Quantitative Structure-activity Relationships
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