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991.
P. Nuno Palma Maria João Bonifácio Ana Isabel Loureiro Patrício Soares‐da‐Silva 《Journal of computational chemistry》2012,33(9):970-986
Alchemical free energy simulations are amongst the most accurate techniques for the computation of the free energy changes associated with noncovalent protein–ligand interactions. A procedure is presented to estimate the relative binding free energies of several ligands to the same protein target where multiple, low‐energy configurational substates might coexist, as opposed to one unique structure. The contributions of all individual substates were estimated, explicitly, with the free energy perturbation method, and combined in a rigorous fashion to compute the overall relative binding free energies and dissociation constants. It is shown that, unless the most stable bound forms are known a priori, inaccurate results may be obtained if the contributions of multiple substates are ignored. The method was applied to study the complex formed between human catechol‐O‐methyltransferase and BIA 9‐1067, a newly developed tight‐binding inhibitor that is currently under clinical evaluation for the therapy of Parkinson's disease. Our results reveal an exceptionally high‐binding affinity (Kd in subpicomolar range) and provide insightful clues on the interactions and mechanism of inhibition. The inhibitor is, itself, a slowly reacting substrate of the target enzyme and is released from the complex in the form of O‐methylated product. By comparing the experimental catalytic rate (kcat) and the estimated dissociation rate (koff) constants of the enzyme‐inhibitor complex, one can conclude that the observed inhibition potency (Ki) is primarily dependent on the catalytic rate constant of the inhibitor's O‐methylation, rather than the rate constant of dissociation of the complex. © 2012 Wiley Periodicals, Inc. 相似文献
992.
993.
1-(2-萘甲基)靛红-5-甲酰胺类化合物通过与底物口袋结合来抑制SARS-3CL 蛋白酶的活性, 而SARS-3CL蛋白酶自身的N端8 肽是作用于蛋白二聚界面的抑制剂. 本文设计同时占据SARS-3CL蛋白酶底物口袋和二聚界面的双功能抑制剂, 通过固相多肽合成方法制备由1-(2-萘甲基)靛红-5-甲酸和N端8肽组成的化合物, 得到不同长度连接链的6 个目标产物. 用显色底物方法测定化合物对SARS-3CL蛋白酶的抑制活性,其中化合物3的活性最高, IC50值(半抑制率)为3.8 μmol·L-1, 连接偶数甘氨酸的活性明显要好于连接奇数甘氨酸的化合物. 用超速离心沉降速率方法研究了化合物3对SARS-3CL蛋白酶聚集状态与活性的调控作用, 其同时具有诱导与抑制二聚的双重能力, 综合调控结果是抑制SARS-3CL蛋白酶的二聚. 这项研究给应用合成的化合物研究酶活性调节机制提供了一个示例. 相似文献
994.
P2Y12受体拮抗剂是一类重要的抗血小板药物,研究分子活性与其结构参数的关系,对于合成新的P2Y12受体拮抗剂具有一定指导作用.选用178个结构多样的P2Y12受体拮抗剂分子作为数据集,随机选取了143个P2Y12受体拮抗剂作为训练集,剩余分子作为检验集.采用多元线性回归(MLR)方法和主成分回归分析(PCA)方法对每个分子的636个分子参数进行线性回归分析.MLR所建模型的结果为:训练集R2=0.800,检验集R2=0.834;PCA模型结果为:训练集R2=0.545,检验集R2=0.665.相比之下MLR法所建模型具有良好的预测性和可靠性.通过模型分析,确定了影响分子活性的关键因素.以上模型对筛选和合成新型高效P2Y12受体拮抗剂提供了一定理论指导. 相似文献
995.
The synthesis and biological evaluation of two series of salicylanilide derivatives on the EGFR and ErbB-2 tyrosine kinases inhibitory activities were conducted.Of the tested compounds those having an additional aryl group substituted on the anilino ring were active on the EGFR tyrosine kinase inhibition(7a-c and 13a,13c,13d,13f).The inhibitory activities were all in the low micromolar or submicromolar range.In addition,compound 13a was found to have dual inhibitory activities both on EGFR and ErbB-2 tyrosine kinases(1.654±1.280 and 7.134±1.265μmol/L). 相似文献
996.
Lin Li Sheng Hai Chang Jun Feng Xiang Qian Li Huan Huan Liang Ya Lin Tang Ying Fang Liu 《中国化学快报》2012,23(1):89-92
PA_C subunit from avian influenza(H5N1) viral RNA polymerase was used in this work as a target in the screening for anti-influenza agents from licorice-derived compounds.As a result,18β-glycyrrhetinic acid was suggested to be PA_C ligand by flexible docking,and was then confirmed by relaxation-edited NMR.The result of ApG primer extension assay indicated that this PA_C ligand can inhibit the polymerase activity,and thus may potentially be valuable as anti-influenza lead compound.This work validated the possibility of screening polymerase inhibitors by using PA_C as a target,and provided a starting point for the further discovery of new anti-influenza drugs. 相似文献
997.
998.
对抑制剂paullones的来源、合成,以及与激酶相互作用的分子机理、选择性、细胞效应进行了综述.指出糖原合成酶激酶-3(GSK-3)是参与糖代谢的主要限速酶之一,人类多种疾病均与其活性调节异常有关;细胞周期蛋白依赖性激酶(CDKs)是一类丝氨酸/苏氨酸蛋白激酶,能够促使细胞进行有序的生长、增殖、休眠或进入凋亡.以CDKs为靶点的药物可以阻断细胞周期,控制癌细胞增殖,从而达到抗肿瘤的目的.Paullones对CDKs和GSK-3均具有良好的选择性,是CDKs和GSK-3的有效抑制剂;迄今为止,文献报道的paullones化合物接近120个. 相似文献
999.
Scanning Kelvin Probe Force Microscopy and Scanning Electrochemical Microscopy were applied for the investigation of localized corrosion on heterogeneous aiming on the investigation of the possible correlation between the local surface potential differences, measured by the Kelvin probe technique in ambient conditions, and corrosion during immersion in a corrosive electrolyte. A model sample mimicking the interaction of Al and Cu in Al alloys was chosen to demonstrate the complementary nature of the information received from SKPFM and SECM. The necessary prerequisites for a future integration of SKP and SECM into a single set‐up are discussed. 相似文献
1000.
K. Leyssens A. Adriaens M.G. Dowsett B. Schotte I. Oloff E. Pantos A.M.T. Bell S.P. Thompson 《Electrochemistry communications》2005,7(12):1265-1270
The focus of this study consists of examining how simultaneous SR-XRD and electrochemical measurements can provide information on the effectiveness of stabilization and storage treatments of copper artefacts in aqueous solution. The electrochemical cell used here was designed for in situ, time resolved SR-XRD studies of corrosion and inhibition studies on cultural heritage materials. Key objectives of the new cell were to monitor corrosion layers on alloys with realistic metallographic structures and to obtain co-incident, time resolved, electrochemical data such as reduction measurements, oxidation measurements and corrosion potential (Ecorr) measurements. Here we present some early results from the cell. Firstly, a correlated SR-XRD and corrosion potential (Ecorr) study of the reduction of nantokite during storage in sodium sesquicarbonate, which shows that the surface chemistry continues to change after Ecorr has stabilized. Secondly, the use of X-ray data to identify specific changes occurring as a function of potential in the forced reduction of a more complex system. 相似文献