凝血酶抑制剂的结构与活性的关系

应用了一种新的预测酶－配体复合物亲和性的方法来研究凝血酶抑制剂的结构－活性关系．凝血酶－抑制剂复合物的三维结构根据模板化合物的晶体结构进行搭建，然后使用程序SCORE计算复合物的亲和性．共分析了3个系列34个抑制剂分子．计算所得的复合物的解离常数与实验值吻合得很好，大大优于用分子力学所给出的结果．通过比较其中两个抑制剂分子的结构和活性，说明了此方法能够定量给出配体分子中每个原子对结合过程的贡献大小，给出十分直接的结构－活性关系．     

凝血酶抑制剂的结构与活性的关系

应用了一种新的预测酶－配体复合物亲和性的方法来研究凝血酶抑制的结构－活性关系。凝血酶－抑制剂复合物的三维结构模板化合物的晶体结构进行搭建，然后使用程序ＳＣＯＲＥ计算复合物的亲和性。共分析了３个系列３４个抑制剂分子。计算所得的复合物的解离常数与实验值吻合得很好，大大优于用分子力学所给出的结果。通过比较其中两个抑制分子的结构和活性，说明了此方法能够定量给出配体分子中每个原子对结合过程的贡献大小，给出十     

三核铁苯甲酸配合物[Fe3O（OBz）6（CH3OH）3]（NO3）（CH3OH）…

测定了三核苯甲苯酸合物［Ｆｅ３Ｏ（ＯＢｚ）６（ＣＨ３ＯＨ）３］（ＮＯ３）（ＣＨ３ＯＨ）２（ＯＢｚ＾－＝苯甲酸根）的电子光谱，应用配体场理论和Ｔ－Ｓ图求得配体场参数１０Ｄｑ－１２４５７ｃｍ＾－１，用ＣＮＤＯ／２方法对其简化模型进行了计算。     

[Ru（MeIm）4L]^2＋（L=iip，tip，2ntz）的电子结构、DNA-键合、构效关系及光谱特征

采用密度泛函的方法,结合导体极化连续模型研究了水溶性二价钌．甲基咪唑类配合物[Ru（MeIm）4iip]^2＋。（1）、[Ru（MeIm）4tip]^2＋0＋（2）和[Ru（MeIm）42ntz]^2＋（3）的电子结构、DNA的键合倾向及构效关系,在水溶液中几何优化的基础上分析了配合物的电子结构特征,并合理解释了配合物与DNA的键合倾向．计算结果表明,在主配体上用噻吩代替咪唑取代基可以有效提高配合物与DNA的键合力;同时,在主配体的骨架上引入强电负性的N原子及NO2基团可以明显降低配合物最低未占据分子轨道能量及前沿分子轨道能量差．基于以上计算结果,预测所设计的配合物3具有最大的DNA键合力常数．另外,详细分析了配合物1、2的构效关系及抗肿瘤作用机理,并预测了配合物3的抗肿瘤活性．最后,用含时密度泛函方法对配合物的电子吸收光谱进行了计算和模拟,并与实验结果进行了对比分析．     

基于分子对接的苯丙素甙（PPGs）类化合物的虚拟筛选和合理设计

采用虚拟化合物生成法对抗肿瘤的苯丙素甙(PPGs)类化合物进行了配体受体对 接研究。以三种不同的骨架结构为基础分别生成了五十个虚拟苯丙素甙(PPGs)类化 合物，并将它们与端粒DNA受体进行分子对接，分析已知结构的对接结果，通过虚 拟筛选的方法得到了一批与受体相互作用能较高并且复合物能量较低的新的有潜力 的活性化合物。该方法可以弥补分子对接研究中，只能计算药物与受体的相互作用 ，无法有效设计新化合物的不足。这种方法在基于结构的药物分子设计中具有重要 的意义。     

Mo（W）－Cu（Ag）－S原子簇化合物的研究现状

本文在研究Ｍｏ（Ｗ）－Ｃｕ（Ａｇ）－Ｓ原子簇化合物的低热固态合成化学基础上，详细地对该类簇合物进行了归纳，从中提出：１．（Ｍ＝Ｍｏ，Ｗ；ｎ＝２，３，４）作为配体中心．２．氧原子在簇合物中仅作为端基，不参与同其他金属成键．３．单个ＭＳ４（Ｍ＝Ｍｏ，Ｗ）基团最多只能键合六个Ｃｕ（Ａｇ）原子，即最大核数为七．４．迄今为止所有Ｍｏ（Ｗ）－Ｃｕ－Ｓ原子簇化合物中Ｃｕ均为＋１价．５．预计合低价态Ｍｏ（Ｗ）的这类簇合物将会有很大进展．     

FeCo2(CO)7(μ3-S)(O[P(SCH2)2]2)的合成与晶体结构

许多化学工作者对单齿膦配体（ＰＰｈ３,ＰＢｕｎ３,ＰＥｔ２Ｐｈ,Ｐ（ＯＥｔ）３,Ｐ（ＯＣ６Ｈ５）３）与母体簇合物ＦｅＣｏ２（ＣＯ）９（μ３－Ｓ）的取代反应进行过详细研究［１－３］,但对双齿膦配体与母体簇合物的取代反应研究报导较少．Ａｉｍｅ［４］合成了含双齿膦配体的簇合物ＦｅＣｏ２（ＣＯ）７（μ３－Ｓ）（Ｐｈ２ＰＣＨ２ＰＰｈ２）,并用１３ＣＮＭＲ和ＩＲ光谱方法对其结构进行了表征．到目前为止,含双齿膦配体的该类簇合物的晶体与分子结构还未见报导．ＲｏｓａｎｎａＲｏｓｓｅｔｔｉ［２］通过研究母体簇合物与…     

双波长光度法配合物组成和稳定常数的测定

利用双波长光度法的选择性这一特点，消除体系中有关物种的干扰，直接测定配体的平衡浓度，基于此结合溶液中物种的分布系数，建立了测定配合物组成和稳定常数的方法，手续简便可靠，试用于Ｃｕ（Ⅱ）－５－Ｂｒ－ＰＡＤＡＰ体系获得了满意的结果。     

铀酰离子和2，3－二羟基－5－甲氧羰基苄基胺羧酰胺螯合剂及小分子配体的三元混配反应研究

用ｐＨ电位法在２５℃，离子强度为０．１（ＫＮＯ３）条件下研究了铀酰离子和六种２，３－二羟基－５－甲氧羰基苄基胺羧酰胺螯合剂、五种在人体血液中含量最高的小分子配体的三元配位反应，得到混配配合物的生成常数，讨论了其稳定性．通过分布计算说明促排过程中可能形成铀酰离子的混配配合物．     

磷脂酶A2吲哚类抑制剂的结构和活性关系

应用一种新的预测酶-配体复合物亲和性的方法来研究磷脂酶A2蚓哚类抑制剂的结构-活性关系．磷脂酶A2-抑制剂复合物的三维结构是用分子模构的方法搭建的，复合物的亲和性由程序SCORE计算．共分析了12个抑制剂分子．计算所得的亲和性和实验测定值吻合得很好，明显优于用CoMFA方法分析同一系列化合物所给出的结果．通过分析SCORE的输出结果，识别出了蚓哚类抑制剂和磷脂酶A2相互作用的关键位点，为设计新型的磷脂酶A2抑制剂提供了指导．     

Relationship between chiroptical properties, structural changes and interactions in enzymes: a computational study on beta-lactamases from class A

Enzyme functions such as catalysis, binding and regulation are directly related to a variety of conformational changes. A sensitive and useful method for their investigation is circular dichroism (CD) and a rotational strength (R) is its fundamental characteristic. In this study, we show how the sensitivity of the mechanisms of rotational strengths to important conformational changes depends on the chromophore environment in two beta-lactamases from class A (from Escherichia coli and B. licheniformis). Rotational strengths have been calculated using the matrix method and including the effects of local environment (LE). X-ray structures (of protein components) of several enzyme-ligand complexes from the catalytic cycle of the TEM-1 enzyme and for both crystallographic monomers of the enzyme from B. licheniformis were used. An analysis of the relative degree of perturbation of the rotational strengths upon local interactions is performed.     

Understanding microscopic binding of human microsomal prostaglandin E synthase-1 with substrates and inhibitors by molecular modeling and dynamics simulation

Microsomal prostaglandin E synthase-1 (mPGES-1) is a promising target for development of next-generation anti-inflammatory drugs. It is crucial for rational design of the next-generation anti-inflammatory drugs to know the three-dimensional (3D) structure of mPGES-1 trimer and to understand how mPGES-1 binds with substrates and inhibitors. In the current work, a 3D structural model of human mPGES-1 trimer has been developed, for the first time, by performing combined homology modeling, molecular docking, and molecular dynamics simulation. The 3D structural model enables us to understand how mPGES-1 binds with its substrates/inhibitors, and the key amino acid residues for the mPGES-1 binding with ligands have been identified. The detailed 3D structures and calculated binding free energies for mPGES-1's binding with substrates and inhibitors are all consistent with available experimental data, suggesting that the 3D model of the mPGES-1 trimer and the enzyme-ligand binding modes are reasonable. The new structural insights obtained from this study should be valuable for rational design of next-generation anti-inflammatory drugs.     

Exploration of enzyme-ligand interactions in CYP2D6 & 3A4 homology models and crystal structures using a novel computational approach

New crystal structures of human CYP2D6 and CYP3A4 have recently been reported, and in this study, we wanted to compare them with previously used homology models with respect to predictions of site of metabolism and ligand-enzyme interactions. The data set consisted of a family of synthetic opioid analgesics with the aim to cover both CYP2D6 and CYP3A4, as most of these compounds are metabolized by both isoforms. The program MetaSite was used for the site of metabolism predictions, and the results were validated by experimental assessment of the major metabolites formed with recombinant CYP450s. This was made on a selection of 14 compounds in the data set. The prediction rates for MetaSite were 79-100% except for the CYP3A4 homology model, which picked the correct site in half of the cases. Despite differences in orientation of some important amino acids in the active sites, the MetaSite-predicted sites were the same for the different structures, with the exception of the CYP3A4 homology model. Further exploration of interactions with ligands was done by docking substrates/inhibitors in the different structures with the docking program GLUE. To address the challenge in interpreting patterns of enzyme-ligand interactions for the large number of different docking poses, a new computational tool to handle the results from the dockings was developed, in which the output highlights the relative importance of amino acids in CYP450-substrate/inhibitor interactions. The method is based on calculations of the interaction energies for each pose with the surrounding amino acids. For the CYP3A4 structures, this method was compared with consensus principal component analysis (CPCA), a commonly used method for structural comparison to evaluate the usefulness of the new method. The results from the two methods were comparable with each other, and the highlighted amino acids resemble those that were identified to have a different orientation in the compared structures. The new method has clear advantages over CPCA in that it is far simpler to interpret and there is no need for protein alignment. The methodology enables structural comparison but also gives insights on important amino acid substrate/inhibitor interactions and can therefore be very useful when suggesting modifications of new chemical entities to improve their metabolic profiles.     

Solvation of the active site of cytochrome P450-cam

Summary Energetically favorable water binding sites in the substrate pocket of cytochrome P450-cam have been predicted by a molecular mechanics method. Binding sites corresponding to all the experimentally observed water sites in this region of the enzyme were located. The calculations also indicate the presence of two further water binding sites. One of these is located in a hydrophobic region of the protein where a water molecule would not bind tightly to the substrate-free enzyme. However, in the substrate-bound enzyme, a water molecule in this region could donate a hydrogen bond of optimum geometry to the carbonyl oxygen atom of the camphor substrate and could therefore contribute to the correct positioning of the comphor substrate for 5-exo-hydroxylation. These calculations also suggest that a steric analogue of camphor, containing an alkyl group which could prevent a water molecule from binding in this region, might inhibit cytochrome P450-cam by forming a more stable enzyme-ligand complex than camphor itself.     

Characterizing Enzyme Cooperativity with Imaging SAMDI-MS

This paper describes a method that combines a microfluidic device and self-assembled monolayers for matrix-assisted laser desorption/ionization mass spectrometry (SAMDI) mass spectrometry to calculate the cooperativity in binding of calcium ions to peptidylarginine deiminase type 2 (PAD2). This example uses only 120 μL of enzyme solution and three fluidic inputs. This microfluidic device incorporates a self-assembled monolayer that is functionalized with a peptide substrate for PAD2. The enzyme and different concentrations of calcium ions are flowed through each of eight channels, where the position along the channel corresponds to reaction time and position across the channel corresponds to the concentration of Ca²⁺. Imaging SAMDI (iSAMDI) is then used to determine the yield for the enzyme reaction at each 200 μm pixel on the monolayer, providing a time course for the reactions. Analysis of the peptide conversion as a function of position and time gives the degree of cooperativity (n) and the concentration of ligand required for half maximal activity (K_0.5) for the Ca²⁺ – dependent activation of PAD2. This work establishes a high-throughput and label-free method for studying enzyme-ligand binding interactions and widens the applicability of microfluidics and matrix-assisted laser desorption/ionization mass spectrometry (MALDI) imaging mass spectrometry.     

An estimation method of binding free energy in terms of ABEEMσπ/MM and continuum electrostatics fused into LIE method

A method is proposed for the estimation of absolute binding free energy of interaction between proteins and ligands. The linear interaction energy method is combined with atom‐bond electronegativity equalization method at σπ level Force field (fused into molecular mechanics) and generalized Born continuum model calculation of electrostatic solvation for the estimation of the absolute free energy of binding. The parameters of this method are calibrated by using a training set of 24 HIV‐1 protease–inhibitor complexes (PDB entry 1AAQ). A correlation coefficient of 0.93 was obtained with a root mean square deviation of 0.70 kcal mol^?1. This approach is further tested on seven inhibitor and protease complexes, and it provides small root mean square deviation between the calculated binding free energy and experimental binding free energy without reparametrization. By comparing the radii of gyration and the hydrogen bond distances between ligand and protein of three training model molecules, the consistent comparison result of binding free energy is obtained. It proves that this method of calculating the binding free energy with appropriate structural analysis can be applied to quickly assess new inhibitors of HIV‐1 proteases. To test whether the parameters of this method can apply to other drug targets, we have validated this method for the drug target cyclooxygenase‐2. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011