4-取代Fentanyl类化合物电子结构及构效关系研究

本文对十一个4-取代Fentanyl类化合物进行了量子化学(INDO)计算, 研究了它们的电子结构及构效关系. 结果表明, 这些化合物同其他Fentanyl类化合物在主要活性部位和电子结构趋势上基本相同. 酰胺氧原子是最重要的负电中心, 哌啶氮原子在季铵化后发挥正电中心作用. 4-取代基的极性基团可能以电荷转移作用或氢键接受体形式与受体极性部位结合, 并能影响其他活性部位电子密度. 另外, 4-取代基的立体因素与疏水因素同生物活性相关.     

3-取代-4-氧-3H-咪唑并[5,1-d][1,2,3,5]四嗪-8-羧酸衍生物抗癌活性的构效关系

采用量子化学和分子力学方法研究3-取代-4-氧-3H-咪唑并[5,1-d] [1,2,3,5]四嗪-8-羧酸衍生物分子结构与抗癌活性的关系.结果表明,3-取代-4-氧-3H-咪唑并[5,1-d] [1,2,3,5]四嗪-8-羧酸衍生物抗癌活性与分子疏水性参数logP、8位取代基R1上的净电荷等因素有关,可通过向8位引入带正电荷取代基的办法来提高先导化合物的抗癌活性.     

2-氰基-3-取代吡啶甲胺基-3-取代丙烯酸乙氧乙酯的合成和除草活性研究

一系列2-氰基-3-取代吡啶甲胺基丙烯酸酯被合成作为光合作用光系统II电子传递抑制剂. 生测发现一些目标化合物表现出很好的除草活性, 如(Z)-2-氰基-3-异丙基-3-(2-烷氧基取代的吡啶-3-基)甲胺基丙烯酸乙氧乙酯. 生测结果表明在吡啶环的2位合适的取代基和丙烯酸酯的3位取代基的体积对除草活性至关重要.     

N-(4'-取代嘧啶-2'-基)-2-甲氧羰基-5-(取代)苯甲酰胺基苯磺酰脲化合物的合成及除草活性研究

为进一步寻找高效、安全和对环境更加友好的除草剂,以商品化除草剂单嘧磺酯为研究基础,对其结构中的苯环5-位取代基作了结构修饰,合成了26个未见文献报道的新型N-(4'-取代嘧啶-2-基)-2-甲氧羰基-5-苯甲酰胺基苯磺酰脲化合物,通过1H NMR、质谱及元素分析确定了化合物的结构.经油菜平皿法及盆栽法测试了所有化合物的除草活性,结果表明,当苯环5-位取代基为苯甲酰胺时,活性较好,其对双子叶植物的除草活性与商品化的甲嘧磺隆相当.     

单重态氧化学 V: 二烷基取代酚光敏氧化反应的研究

本文研究了2,6-二甲基酚、2,4-二甲基酚及3,4-二甲基酚的光敏氧化反应, 应用竹红菌甲素作敏化剂匹配高压钠灯首次提供了二烷基取代酚同单重态氧发生化学反应的例证, 并测定了它们对单重态氧的反应速度常数, 其反应活性顺序为:BHT>2,4-DMP>3,4-DMP>DBP>2,6-DMP.二烷基取代酚同单重态氧可能通过1,4-环加成反应的机理, 再经重排生成最终产物.     

单重态氧化物 IV: 6-取代-1,4-环辛二烯的光敏氧化反应

6-取代-1,4-环辛二烯与单重态氧立体有选择地氧化成顺式5,8-和反式5,6-二取代-1,3-环辛二烯的含氧衍生物. 依据产物的分子结构推知, 6-取代-1,4-环辛二烯发生“ene"反应时的优势构象不同于环辛烷, 而是具有角张力的扭曲构象(1), 这为研究环烯的分子构象提供了一种实验方法.用Monroe法测定了6-取代-1,4-环辛二烯对单重态氧反应的β值. 其反应活性顺序为:3>1>4>1, 5-环辛二烯>2>5. 表明推电子取代基增加了同单重态氧反应的能力, 而吸电子取代基则降低了同单重态氧的反应能力, 但是不论取代基性质如何, 都不能改变“ene"反应的本质.     

单重态氧化物 IV: 6-取代-1,4-环辛二烯的光敏氧化反应

6-取代-1,4-环辛二烯与单重态氧立体有选择地氧化成顺式5,8-和反式5,6-二取代-1,3-环辛二烯的含氧衍生物. 依据产物的分子结构推知, 6-取代-1,4-环辛二烯发生“ene"反应时的优势构象不同于环辛烷, 而是具有角张力的扭曲构象(1), 这为研究环烯的分子构象提供了一种实验方法.用Monroe法测定了6-取代-1,4-环辛二烯对单重态氧反应的β值. 其反应活性顺序为:3>1>4>1, 5-环辛二烯>2>5. 表明推电子取代基增加了同单重态氧反应的能力, 而吸电子取代基则降低了同单重态氧的反应能力, 但是不论取代基性质如何, 都不能改变“ene"反应的本质.     

单重态氧化学 V: 二烷基取代酚光敏氧化反应的研究

本文研究了2,6-二甲基酚、2,4-二甲基酚及3,4-二甲基酚的光敏氧化反应, 应用竹红菌甲素作敏化剂匹配高压钠灯首次提供了二烷基取代酚同单重态氧发生化学反应的例证, 并测定了它们对单重态氧的反应速度常数, 其反应活性顺序为:BHT>2,4-DMP>3,4-DMP>DBP>2,6-DMP.二烷基取代酚同单重态氧可能通过1,4-环加成反应的机理, 再经重排生成最终产物.     

N-(4'-取代嘧啶-2'-基)-2-甲氧羰基-5-(取代)苯甲酰胺基苯磺酰脲化合物的合成及除草活性研究

为进一步寻找高效、安全和对环境更加友好的除草剂, 以商品化除草剂单嘧磺酯为研究基础, 对其结构中的苯环5-位取代基作了结构修饰, 合成了26个未见文献报道的新型N-(4'-取代嘧啶-2'-基)-2-甲氧羰基-5-苯甲酰胺基苯磺酰脲化合物, 通过¹H NMR、质谱及元素分析确定了化合物的结构. 经油菜平皿法及盆栽法测试了所有化合物的除草活性, 结果表明, 当苯环5-位取代基为苯甲酰胺时, 活性较好, 其对双子叶植物的除草活性与商品化的甲嘧磺隆相当.     

羟甲芬太尼对离体器官阿片受体亚型的选择性

受体结合试验已经提示羟甲芬太尼可能是μ受体激动剂。本文研究羟甲芬太尼对离体器官阿片受体的作用。羟甲芬太尼对豚鼠迴肠与小鼠输精管电刺激引起的收缩有很强的抑制作用,它们的IC_(50)分别为0.15nM与0.89nM。在豚鼠迴肠与小鼠输精管,羟甲芬太尼的抑制作用容易被纳洛酮(μ受体拮抗剂)和Mr.2266(μ受体和k受体拮抗剂)拮抗,表明该化合物选择性作用于豚鼠迴肠与小白鼠输精管μ受体。和μ激动剂(D-Ala~2,MePhe~4,Gly-ol~5)脑啡肽一样,羟甲芬太尼在大鼠输精管只呈现激动活性,没有拮抗作用。在兔输精管(含单一的k受体),羟甲芬太尼作用很弱,IC_(50)高达149nM,比豚鼠迴肠上的作用弱1000倍。这些结果进一步证明羟甲芬太尼是一个强效的选择性μ受体激动剂。     

Structural changes by sulfoxidation of phenothiazine drugs

Summary The side-chain conformations of psychoactive phenothiazine drugs in crystals are different from those of biologically inactive ring sulfoxide metabolites. This study examines the potential energies, molecular conformations and electrostatic potentials in chlorpromazine, levomepromazine (methotrimeprazine), their sulfoxide metabolites and methoxypromazine. The purpose of the study was to examine the significance of the different crystal conformations of active and inactive phenothiazine derivatives, and to determine why phenothiazine drugs lose most of their biological activity by sulfoxidation. Quantum mechanics and molecular mechanics calculations demonstrated that conformations with the side chain folded over the ring structure had lowest potential energy in vacuo, both in the drugs and in the sulfoxide metabolites. In the sulfoxides, side chain conformations corresponding to the crystal structure of chlorpromazine sulfoxide were characterized by stronger negative electrostatic potentials around the ring system than in the parent drugs. This may weaken the electrostatic interaction of sulfoxide metabolites with negatively charged domains in dopamine receptors, and cause the sulfoxides to be virtually inactive in dopamine receptor binding and related pharmacological tests.     

Stereoelectronic properties of spiroquinazolinones in differential PDE7 inhibitory activity

A detailed computational study on a series of spiroquinazolinones showing phosphodiesterase 7 (PDE7) inhibitory activity was performed to understand the binding mode and the role of stereoelectronic properties in binding. Our docking studies reproduced the essential hydrogen bonding and hydrophobic interactions for inhibitors of this class of enzymes. The N1 proton of the quinazolinone scaffold was involved in H-bonding to an amide side chain of the conserved glutamine residue in the active site. The central bicyclic ring of the molecules showed hydrophobic and pi-stacking interactions with hydrophobic and aromatic amino acid residues, respectively, present in the PDE7 active site. The docked conformations were optimized with density functional theory (DFT) and DFT electronic properties were calculated. Comparison of molecular electrostatic potential (MEP) plots of inhibitors with the active site of PDE7 suggested that the electronic distribution in the molecules is as important as steric factors for binding of the molecules to the receptor. The hydrogen bonding ability and nucleophilic nature of N1 appeared to be important for governing the interaction with PDE7. For less active inhibitors (pIC(50) < 6.5), the MEP maximum at N1 of the spiroquinazolinone ring was high or low based on the electronic properties of the substituents. All the more active molecules (pIC(50) > 6.5) had MEP highest at N3, not N1. Efficient binding of these inhibitors may need some rearrangement of side chains of active-site residues, especially Asn365. This computational modeling study should aid in design of new molecules in this class with improved PDE7 inhibition.     

Physical nature of intermolecular interactions within cAMP-dependent protein kinase active site: differential transition state stabilization in phosphoryl transfer reaction

The origin of enzyme catalytic activity may be effectively explored within the nonempirical theory of intermolecular interactions. The knowledge of electrostatic, exchange, delocalization, and correlation components of the transition state and substrates stabilization energy arising from each enzyme active site residue allows to examine the most essential physical effects involved in enzymatic catalysis. Consequently, one can build approximate models of the catalytic activity in a systematic and legitimate manner. Whenever the dominant role of electrostatic interactions is recognized or assumed, the properties of an optimal catalytic environment could be simply generalized and visualized by means of catalytic fields that, in turn, aids the design of new catalysts. Differential transition state stabilization (DTSS) methodology has been applied herein to the phosphoryl transfer reaction catalyzed by cAMP-dependent protein kinase (PKA). The MP2 results correlate well with the available experimental data and theoretical findings indicating that Lys72, Asp166, and the two magnesium ions contribute -22.7, -13.3, -32.4, and -15.2 kcal/mol to differential transition state stabilization, respectively. Although all interaction energy components except that of electron correlation contribution are meaningful, the first-order electrostatic term correlates perfectly with MP2 catalytic activity. Catalytic field technique was also employed to visualize crucial electrostatic features of an ideal catalyst and to compare the latter with the environment provided by PKA active site. The map of regional electronic chemical potential was used to analyze the unfavorable catalytic effect of Lys168. It was found that locally induced polarization of TS atoms thermodynamically destabilizes electrons, pulling them to regions displaying higher electronic chemical potential.     

A proposed common spatial pharmacophore and the corresponding active conformations of some peptide leukotriene receptor antagonists

Summary Molecular modeling studies were carried out by a combined use of conformational analysis and 3D-QSAR methods to identify molecular features common to a series of hydroxyacetophenone (HAP) and non-hydroxyacetophenone (non-HAP) peptide leukotriene (pLT) receptor antagonists. In attempts to develop a ligand-binding model for the pLT receptor, the Apex-3D program was used to identify biophoric structural patterns that are common to 13 diverse sets of compounds showing different levels of biological activity. A systematic conformational analysis was carried out to obtain sterically accessible conformations for these flexible compounds. Apex-3D was then utilized to propose common biophoric regions based on the selection of one of several conformations (MOPAC-minimized AM1) from each compound's data set that best fits the biophoric pattern and the resulting superimposition with all the other data-set compounds. Apex-3D identified three common biophoric features important for activity: one as the hydroxyl, acetyl, carbonyl and carboxyl groups, which mimic the acid-binding region of an agonist, the other as the hydrogen-bond donating site, and the third part is represented by a plane in which lipophilic aromatic groups align. The structure-activity relationships were then assessed by using the 3D-QSAR model. A common biophore model is proposed from the Apex-3D analysis which may be useful in designing new pLT antagonists. Molecular volumes and electrostatic potential similarities were also calculated in order to obtain the important structural requirements for the activity.     

Use of Molecular Electrostatic Potentials for Analysis of Anticonvulsant Activities of Phenylsuccinimides

Abstract

The present study was performed on a group of 27 derivatives of phenylsuccinimides, of which only 12 were active against maximal electrical shock in spite of the structural similarities of these compounds. The work consisted of four main parts: 1. crystallographic investigations of a subset of chosen compounds; 2. conformational analysis of characteristic molecules from the investigated series, performed by means of molecular mechanics calculations; 3. molecular orbital optimization of all the molecules using the MNDO method starting with conformations obtained in 2; 4. molecular electrostatic potential (MEP) analysis which was performed on the semiempirical (MNDO) and ab initio levels. This research showed that MEP maps provide a signature that distinguishes between active and inactive compounds. There are MEP minima close to the two carbonyl oxygens of the imide ring, and although the magnitude of the difference between the two minima is approximately constant, the sign of the difference provides an activity index. The initial orientations of phenylsuccinimide molecules in relation to the receptor are not equivalent and they depend on the potential distribution around both the succinimide molecules and around the receptor. In the active compounds the negative potential difference at the discussed points most probably influences the initial set-up of the molecules in relation to the receptor and results in a considerably higher probability of the molecules being bound at the right place on the receptor.     

Quantitative structure-activity relationships for calmodulin inhibitors

Using the discriminant analysis method, we completely distinguished 24 calmodulin inhibitors in three groups, as classified by Zimmer et al. The resultant discriminant functions distinguished the three groups in terms of positive potential surface area on the side chain, as well as the total and neutral surface areas on the ring in the inhibitor molecules. Group assignment of additional calmodulin inhibitors from other sources was then estimated according to the discriminant functions. The relationship between structure and inhibitory potency on calmodulin-activated phosphodiesterase for group I inhibitors, together with those estimated, was studied using the adaptive least squares method with several parameters dependent on molecular conformations. A "best conformer" was selected for each inhibitor on the basis of quantitative structure-activity relationship (QSAR). The results of QSAR analysis of group I inhibitors showed that hydrophobicity was important for the ring moiety but not for the side chain. The negative potential surface area of the side chain is necessary for activity. It is desirable for the nitrogen atom in the side chain, which is considered the center of the negative potential area, to be located far from the ring moiety. Thus, the ring moiety and side chain may possibly play different roles in interactions with the receptor system.     

Multiple flexible alignment with SEAL: a study of molecules acting on the colchicine binding site

An extension of the steric and electrostatic alignment alignment (SEAL) method (MultiSEAL) is described that allows the overlay of multiple molecules and conformations. The method is well-suited for the systematic study of possible alignments, also revealing information about the conformational energies associated with a given overlay. It has been tested on three examples: angiotensin II antagonists, 5-HT3 antagonists, and dopaminergic compounds. The utility of the method is further demonstrated in an analysis of molecules that putatively bind to the colchicine site of tubulin. On the basis of its overlay with colchicine, allocolchicine, 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone, and combretastatin A-4, it appears that 2-methoxyestradiol (2-ME) is unlikely to fit the colchine site properly. The weak antimitotic activity of 2-ME may be explained by its partial fit in the site.     

紫杉醇类似物C13侧链手性构型与活性关系的从头算研究

应用从头算RHF/STO-3G方法优化了四个紫杉醚异构体,在RHF/6-31G*水平进行单点计算,并计算了四个分子的静电势。分子立体构型表明:C13侧链上2 R构型的2-OH和3 S构型的3-NH均处于分子外侧,有利于与受体极性基团结合;2 S构型的2-OH和3 R构型的3-NH在分子的内侧,不利于与受体极性基团结合。静电势的结果表明,R构型的2-OH和S构型的3-NH可以产生相应的负电势区域。当C13侧链为天然构型(2 R,3 S)时,分子可能以双基结合的方式通过负静电势区域与受体作用,活性较高。     

Comparison of a 3D-model of the classical α-scorpion toxin V from Leiurus quinquestriatus quinquestriatus with other scorpion toxins

In the present paper, a study of classical and insect alpha-scorpion toxins is described. A homology model of the classical alpha-toxin LqqV from Leiurus quinquestriatus quinquestriatus was developed. The model was compared to stable and energetically favourable conformations of AaHII from Androctonus australis Hector and LqhalphaIT from Leiurus quinquestriatus hebraeus, which are the most active alpha-toxins in mammals and insects. The conformations were retrieved from molecular dynamics simulations of known structures. The model of LqqV shows a C-terminal conformation similar to LqhalphaIT. This is mainly caused by electrostatic interactions between Lys10 /Lys60 and Glu59, which are comparable to the cation-pi interactions of Tyr10 and Arg64 in LqhalphaIT. During the simulations the structures of AaHII and LqqV were stabilised through electrostatic interactions between Glu32 and Lys50 and especially the loop adjacent to the alpha-helix is affected, which is in contrast to LqhalphaIT. When the molecular electrostatic potentials of the toxins were studied, a possibly important difference between the classical alpha-toxins and the insect alpha-toxin LqhalphaIT was found in the area around Lys30 and Arg56 of AaHII, where a positive potential is missing in LqhalphaIT. A large negative potential caused by Asp3, Glu15 and Asp19 in LqhalphaIT is also unique for this toxin. It is proposed that Arg18, which is important for activity of LqhalphaIT, restricts the negative potential in this area and is not essential for toxins where negatively charged residues in comparable positions are not present.     

某些海生毒素(TTX、STX)对钠离子通道的作用研究

研究了河豚毒素（TTX）和石房蛤毒素（STX）及其衍生物的电子结构和分子构型．结果表明TTX中的胍基和半缩醛内酯环以及STX中的两个胍基均形成具有一个碳正电中心的两个高极性平面构型，三角形三个顶点的氮和氧原子分别带有大量负电荷．TTX和STX具有相似的电子结构和空间结构．对于TTX和STX及其衍生物的作用机理以及分子构型与毒性之间的关系也进行了讨论．