[Co(2,3-tri)(amp)Cl]^2^+几何经式异构体取代与重排规律、构效关系的研究

对[Co(2,3-tri)(amp)Cl]^2^+四个几何经式异构体在不同条件下的取代及重排反应进行了详细的考察。因二元胺中吡啶环造成的空间拥塞,使cis异构体碱水解速度比trans异构体约快100倍,控制碱水解实验结果表明,每一异构体的水解产物均含四个经式异构体,且具有相同分布。实验过程中未观察到面式异构体。在二甲亚砜中加热的重排反应中,异构体m1表现出最高的反应性,cis异构体均首先转化为trans异构体m3,而后可观察到trans异构体m3与m4的平衡。利用时间分辨核磁共振仪测定了氘代水里各异构体中各活性氢的氘代化速度。反应活性最低的异构体m4具有氘代速度最快的活性氢,当这些活性氢完全氘代化时仍未见其水解或重排产物;而相同实验条件下异构体m1或m2中相应活性氢的氘代化速度则要缓慢得多,但同时可观察到水解和重排产物。这说明在碱催化水解过程中氘代速度快的活性氢与异构体的反应性并非正比关系,然而活性氢的氘代化是观察到异构体水解重排的必要条件。利用量子化学从头计算法在赝势基组RHF/LANL2DZ的水平上对该体系各异构体进行了结构优化计算,与对应异构体的晶体结构参数比较,一般相对误差不超过3%,从能量角度来看,cis异构体比trans异构体高出约4kJ/mol,而面式异构体则至少比经式异构体高约17kJ/mol;考虑溶剂化影响,一般约低5kJ/mol。考察结构参数结果显示,结构变形性参数能较好地解释异构体反应活性。     

HAsO~2异构体结构、相对稳定性与体系势能面

在MP2/6-311++G(d,p)和QCISD(T)/6-311++G(3df,2p)(单点)水平下计算得到了包括9个异构体和10个过滤态的HAsO~2体系势能面。在势能面上，异构体cis-HOAsO(E1)的能量是最低的，其次是trans-HOAsO(E2)和HAsO(O)(C~2~V,E3)，能量分别比cis-HOAsO高13.15和192.74kJ/mol。根据体系的势能面，异构体E1，E3及cis-HOOAs(E6),trans-HOOAs(E5)具有一定的动力学稳定性，在实验中应该可以观测到。AsH和O~2反应的第一步产物将会异构化为具有较高动力学稳定性的异构体E3；而OH和AsO反应可直接生成E1。计算结果与HPO~2,HPS~2,HNO~2,HNS~2等价电子相同的分子的势能面进行了比较。     

[Co(2,3-tri)(amp)Cl]~(2+)几何经式异构体取代与重排规律、构效关系的研究

对[Co（2,3-tri）（amp）Cl]2+四个几何经式异构体在不同条件下的取代及重排反应进行了详细的考察.因二元胺中吡啶环造成的空间拥塞,使cis异构体碱水解速度比trans异构体约快100倍,控制碱水解实验结果表明,每一异构体的水解产物均含四个经式异构体,且具有相同分布.实验过程中未观察到面式异构体.在二甲亚砜中加热的重排反应中,异构体m1表现出最高的反应性,cis异构体均首先转化为trans异构体m3,而后可观察到trans异构体m3与m4的平衡.利用时间分辨核磁共振仪测定了在氘代水里各异构体中各活性氢的氘代化速度.反应活性最低的异构体m4具有氘代速度最快的活性氢,当这些活性氢完全氘代化时仍未见其水解或重排产物;而相同实验条件下异构体m1或m2中相应活性氢的氘代化速度则要缓慢得多,但同时可观察到水解和重排产物.这说明在碱催化水解过程中氘代速度快的活性氢与异构体的反应性并非正比关系,然而活性氢的氘代化是观察到异构体水解重排的必要条件.利用量子化学从头计算法,在赝势基组RHF/LANL2DZ的水平上对该体系各异构体进行了结构优化计算,与对应异构体的晶体结构参数比较,一般相对误差不超过3％.从能量角度来看,cis异构体比trans异构体高出约4kJ/mol,而面式异构体则至少比经式异构体高约17kJ/mol;考虑溶剂化     

N5H5异构体的结构与稳定性的理论研究

采用密度泛函理论的B3LYP方法在6-311++G**基组水平上对N5H5氮氢化合物异构体可能存在的构型进行了几何优化, 得到23种稳定异构体, 并研究了这些异构体间可能的互变异构情况. 为了讨论N5H5异构体作为含能材料候选物质的可能性, 还采用了G3B3方法计算了能量, 并且计算了异构体的生成热(⊿Hf,298).结果表明, 在23种异构体中链状异构体最稳定, 四元环四氮烷异构体最不稳定, 存在一个N=N双键的异构体较同类异构体能量低, 较为稳定; N5H5氮氢化合物的生成热均为正, 其中异构体E1生成热最高. 估算了N5H5的摩尔体积, 由密度公式ρ=MT/Vmol,得到E1 的密度最大.     

苄基保护的L-核苷的制备

作为主要的抗病毒药物,核苷类化合物得到了广泛应用.近年来的研究发现,一些L-型异构体比其相应的D-型异构体具有更高的抗病毒活性和更低的毒性[1],新型L-构型核苷类化合物的设计、合成的相关研究受到普遍关注.     

紫杉醚与αβ微管蛋白的分子对接

采用Insight II/Affinity对紫杉醚与αβ微管蛋白进行分子对接, 共得到10个对接构象. 应用密度泛函B3LYP/6-31G 方法计算对接口袋构象的结合能, 筛选出结合能达-190.53 kJ·mol-1的最优对接构象5. 通过构象分析建立紫杉醚与受体结合的作用模型, 结果表明, 在活性口袋的底部紫杉醚与受体间的作用主要是疏水作用, 而在活性口袋的顶部两者间主要是氢键作用. 氢键作用位置可分为A和B两个作用区, 其中A区有3个氢键, 由C13侧链分别与受体的ASP26和ARG369作用形成; B区也有3个氢键, 是由紫杉醚母环上的极性基团分别与受体的THR276、ARG278和GLN282作用产生的. 紫杉醚与αβ微管蛋白间形成的6个氢键可以有效地将紫杉醚固定在活性口袋中.     

HBO2异构体的结构和相对稳定性

用ab initio方法在MP2/6 311＋＋G(d,p)水平下优化得到了HBO2体系的若干异构体和过渡态，并在QCISD(t)/6 311＋＋G(3df,2p)//MP2/6 311＋＋G(d,p)水平下进行了单点能量校正.对计算结果的分析表明，无论是在热力学还是在动力学上，具有链状结构的HOBO异构体(E1)是势能面上最稳定的结构，并对E1的电子结构进行了分析；另一具有C2v对称性的HBO(O)结构的异构体(E2)的能量比E1高381.72 kJ•mol－1，由于E2处于一个较深的势垒中，因此是比较稳定的，可以推断，在适合的实验中应该可以观察到异构体E2.     

八种黄酮类天然产物对高危型HPV16/18 E6蛋白的分子对接研究

宫颈癌以其高发病率和高死亡率严重危害女性健康,传统治疗手段有效率低且治疗过程给患者带来极大痛苦。近年来,许多天然植物来源化合物已被确定为治疗和预防宫颈癌的有希望的药物来源,但天然产物治疗癌症的具体作用机制尚未明确。因此,本文选取了8种黄酮类天然小分子抑制剂,分别与高危型HPV16/18 E6蛋白重要位点LxxLL疏水口袋进行分子对接研究,以期探索天然产物抗宫颈癌的作用机制。对接分析显示,这些天然产物均与HPV18E6蛋白LxxLL疏水口袋产生较强相互作用,与HPV16 E6蛋白对接时,木犀草素则比其他7种黄酮类化合物结合得更为深入,这些相互作用可能有助于p53功能的恢复。对接分析有助于理解蛋白质-配体相互作用的分子机制,为设计治疗HPV感染的新药提供依据。     

HAsS2异构体结构与稳定性

在MP2/6-311++G(d,p)和QCISD(t)/6-311++G(3df,2p)(单点)水平下计算得到9个异构体和10个过渡态的HAsS₂体系势能面.异构体cis-HSAsS(E1)的能量最低,其次是trans-HSAsS(E2)、具有AsSS三元环的立体HAs(S)S(C_{s,E3)和HAs(S)S(C2v,E4)结构的异构体,能量分别比cis-HSAsS高1.46,60.78和93.63kJ/mol.根据体系的势能面,异构体E1,E2,E3和E4具有一定的动力学稳定性.AsH和S2第一步反应产物将会异构化为具有较高动力学稳定性的异构体E3,而SH和AsS第一步反应产物将会异构化为E1.计算结果与HNO2,HNS2,HPO2,HPS2和HAsO2等价电子相同的分子的势能面进行了比较.}     

吲哚衍生物类VEGFR-2酪氨酸激酶抑制剂的从头设计

以血管内皮生长因子受体-2(VEGFR-2)酪氨酸激酶的晶体结构为基础, 采用从头药物设计方法, 设计了一系列吲哚类化合物, 并用类药性和分子对接进行了筛选, 最后得到10个对接能量较低的化合物分子, 对具有最低结合能的化合物与VEGFR-2酪氨酸激酶的复合物进行了10 ns的分子动力学模拟, 并对其结合模式进行了分析. 这些化合物结构新颖, 可能作为抗肿瘤的先导化合物或候选药物. 本文结果为VEGFR-2酪氨酸激酶抑制剂的进一步改造、 设计及合成提供了理论基础, 并有助于开发高活性和高选择性的抗肿瘤药物.     

Dynamic mechanism of E2020 binding to acetylcholinesterase: a steered molecular dynamics simulation

The unbinding process of E2020 ((R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidine) leaving from the long active site gorge of Torpedo californica acetylcholinesterase (TcAChE) was studied by using steered molecular dynamics (SMD) simulations on a nanosecond scale with different velocities, and unbinding force profiles were obtained. Different from the unbinding of other AChE inhibitors, such as Huperzine A that undergoes the greatest barrier located at the bottleneck of the gorge, the major resistance preventing E2020 from leaving the gorge is from the peripheral anionic site where E2020 interacts intensively with several aromatic residues (e.g., Tyr70, Tyr121, and Trp279) through its benzene ring and forms a strong direct hydrogen bond and a water bridge with Ser286 via its O24. These interactions cause the largest rupture force, approximately 550 pN. It was found that the rotatable bonds of the piperidine ring to the benzene ring and dimethoxyindanone facilitate E2020 to pass the bottleneck through continuous conformation change by rotating those bonds to avoid serious conflict with Tyr121 and Phe330. The aromatic residues lining the gorge wall are the major components contributing to hydrophobic interactions between E2020 and TcAChE. Remarkably, these aromatic residues, acting in three groups as "sender" and "receiver", compose a "conveyer belt" for E2020 entering and leaving the TcAChE gorge.     

Molecular docking and competitive binding study discovered different binding modes of microsomal prostaglandin E synthase-1 inhibitors

Microsomal prostaglandin E synthase-1 (mPGES-1) is a newly recognized therapeutic target for the treatment of inflammation, pain, cancer, atherosclerosis, and stroke. Many mPGES-1 inhibitors have been discovered. However, as the structure of the binding site is not well-characterized, none of these inhibitors was designed based on the mPGES-1 structure, and their inhibition mechanism remains to be fully disclosed. Recently, we built a new structural model of mPGES-1 which was well supported by experimental data. Based on this model, molecular docking and competition experiments were used to investigate the binding modes of four representive mPGES-1 inhibitors. As the inhibitor binding sites predicted by docking overlapped with both the substrate and the cofactor binding sites, mPGES-1 inhibitors might act as dual-site inhibitors. This inhibitory mechanism was further verified by inhibitor-cofactor and inhibitor-substrate competition experiments. To investigate the potency-binding site relationships of mPGES-1 inhibitors, we also carried out molecular docking studies for another series of compounds. The docking results correlated well with the different inhibitory effects observed experimentally. Our data revealed that mPGES-1 inhibitors could bind to the substrate and the cofactor binding sites simultaneously, and this dual-site binding mode improved their potency. Future rational design and optimization of mPGES-1 inhibitors can be carried out based on this binding mechanism.     

Prediction of the binding site of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine in acetylcholinesterase by docking studies with the SYSDOC program

Summary In the preceding paper we reported on a docking study with the SYSDOC program for predicting the binding sites of huperzine A in acetylcholinesterase (AChE) [Pang, Y.-P. and Kozikowski, A.P., J. Comput.-Aided Mol. Design, 8 (1994) 669]. Here we present a prediction of the binding sites of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine (E2020) in AChE by the same method. E2020 is one of the most potent and selective reversible inhibitors of AChE, and this molecule has puzzled researchers, partly due to its flexible structure, in understanding how it binds to AChE. Based on the results of docking 1320 different conformers of E2020 into 69 different conformers of AChE and on the pharmacological data reported for E2020 and its analogs, we predict that both the R- and the S-isomer of E2020 span the whole binding cavity of AChE, with the ammonium group interacting mainly with Trp⁸⁴, Phe³³⁰ and Asp⁷², the phenyl group interacting mainly with Trp⁸⁴ and Phe³³⁰, and the indanone moiety interacting mainly with Tyr⁷⁰ and Trp²⁷⁹. The topography of the calculated E2020 binding sites provides insights into understanding the high potency of E2020 in the inhibition of AChE and provides hints as to possible structural modifications for identifying improved AChE inhibitors as potential therapeutics for the palliative treatment of Alzheimer's disease.     

Role of bridging water molecules in GSK3β-inhibitor complexes: insights from QM/MM, MD, and molecular docking studies

The role of water molecules is increasingly gaining interest in drug design, and several studies have highlighted their paramount contributions to the specificity and the affinity of ligand binding. In this study, we employ the two-layer ONIOM-based quantum mechanics/molecular mechanics (QM/MM) calculations, molecular dynamics (MD) simulations, and molecular docking studies to investigate the effect of bridging water molecules at the GSK3β-inhibitors interfaces. The results obtained from the ONIOM geometry optimization and AIM analysis corroborated the presence of bridging water molecules that form hydrogen bonds with protein side chain of Thr138 and/or backbone of Gln185, and mediate interactions with inhibitors in the 10 selected GSK3β-inhibitor complexes. Subsequently, MD simulations carried out on a representative system of 1R0E demonstrated that the bridging water molecule is stable at the GSK3β-inhibitor interface and appears to contribute to the stability of the protein-inhibitor interactions. Furthermore, molecular docking studies of GSK3β-inhibitor complexes indicated that the inhibitors can increase binding affinities and the better docked conformation of inhibitors can be obtained by inclusion of the bridging water molecules, especially for the flexible inhibitors, in docking experiments into individual protein conformations. Our results elucidate the importance of bridging water molecules at the GSK3β-inhibitor interfaces and suggest that they might prove useful in rational drug design.     

Fluorescence properties of pyrylretinol

A fluorescent analog of retinol, 3,7-dimethyl-9-(1-pyryl)-2E,4E,6E,8E-nonatetr aene-1-ol (referred to as pyrylretinol, or 1) has been synthesized. The fluorescence properties (e.g. quantum yield, lifetime, steady-state anisotropy, and excitation/emission spectra) of this compound in various organic solvents and in dimyristoylphosphatidylcholine (DMPC) liposomes have been studied, and the results are compared with those obtained from 3-methyl-5-(1-pyryl)-2E,4E-pentadiene-1-ol (2), which has the same fused aromatic ring system but a much shorter acyclic chain. 1 and 2 form excimer in aqueous media and fluorescence anisotropies of both 1 and 2 in DMPC liposomes exhibit an abrupt decrease at approximately 21-23 degrees C, which coincides with the main phase transition temperature of DMPC liposomes, indicating that both compounds may be a useful membrane probe. In addition, the binding and quenching capability of pyrylretinol (1) to bovine serum albumin has been investigated. Pyrylretinol (1) binds with BSA with a binding constant of 3.6 x 10(4) M-1, although the value is somewhat lower than that obtained for retinol (3.06 x 10(5) M-1). Pyrylretinol (1) also quenches the BSA intrinsic fluorescence with the quenching rate constant of 1.67 x 10(13) M-1 s-1 and the value is lower than that obtained for retinol (4.06 x 10(13) M-1 s-1). The binding and quenching studies suggest that pyrylretinol (1) may serve as a useful fluorescence probe for structure/function studies of different retinoid binding proteins.     

Acetylcholinesterase complexed with bivalent ligands related to huperzine a: experimental evidence for species-dependent protein-ligand complementarity

Acetylcholinesterase (AChE) inhibitors improve the cognitive abilities of Alzheimer patients. (-)-Huperzine A [(-)-HupA], an alkaloid isolated from the club moss, Huperzia serrata, is one such inhibitor, but the search for more potent and selective drugs continues. Recently, alkylene-linked dimers of 5-amino-5,6,7,8-tetrahydroquinolinone (hupyridone, 1a), a fragment of HupA, were shown to serve as more potent inhibitors of AChE than (-)-HupA and monomeric 1a. We soaked two such dimers, (S,S)-(-)-bis(10)-hupyridone [(S,S)-(-)-2a] and (S,S)-(-)-bis(12)-hupyridone [(S,S)-(-)-2b] containing, respectively, 10 and 12 methylenes in the spacer, into trigonal TcAChE crystals, and solved the X-ray structures of the resulting complexes using the difference Fourier technique, both to 2.15 A resolution. The structures revealed one HupA-like 1a unit bound to the "anionic" subsite of the active-site, near the bottom of the active-site gorge, adjacent to Trp84, as seen for the TcAChE/(-)-HupA complex, and the second 1a unit near Trp279 in the "peripheral" anionic site at the top of the gorge, both bivalent molecules thus spanning the active-site gorge. The results confirm that the increased affinity of the dimeric HupA analogues for AChE is conferred by binding to the two "anionic" sites of the enzyme. Inhibition data show that (-)-2a binds to TcAChE approximately 6-7- and > 170-fold more tightly than (-)-2b and (-)-HupA, respectively. In contrast, previous data for rat AChE show that (-)-2b binds approximately 3- and approximately 2-fold more tightly than (-)-2a and (-)-HupA, respectively. Structural comparison of TcAChE with rat AChE, as represented by the closely related mouse AChE structure (1maa.pdb), reveals a narrower gorge for rat AChE, a perpendicular alignment of the Tyr337 ring to the gorge axis, and its conformational rigidity, as a result of hydrogen bonding between its hydroxyl group and that of Tyr341, relative to TcAChE Phe330. These structural differences in the active-site gorge explain the switch in inhibitory potency of (-)-2a and 2b and the larger dimer/(-)-HupA potency ratios observed for TcAChE relative to rat AChE. The results offer new insights into factors affecting protein-ligand complementarity within the gorge and should assist the further development of improved AChE inhibitors.     

Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: synthesis and pharmacological properties of 4'-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-ben zoazepine-1-carbonyl]benzanilide and 4'-[5-(substituted methyl)-2,3-dihydro-1H-1-benzoazepine-1- carbonyl]benzanilide derivatives

Arginine vasopressin (AVP) has a dual action, i.e. vasoconstriction and water reabsorption via V1A and V2 receptors, and may play a role in a number of diseases, including congestive heart failure (CHF), hypertension, renal disease, edema, and hyponatremia. We have attempted to develop a new series of AVP antagonists for both V1A and V2 receptors based on the hypothesis that the blockade of both V1A and V2 receptors might be beneficial to CHF patients. In this report, a series of compounds structurally related to 4'-[5-(substituted methylidene)-2,3,4,5-tetrahydro-1H-1-benzoazepine-1-carbonyl ]benzanilide (exo-olefin isomer) and 4'-[5-(substituted methyl)-2,3-dihydro-1H-1-benzoazepine-1-carbonyl]benzanilide (endo-olefin isomer) were synthesized and examined to have AVP antagonist activity for both V1A and V2 receptors. As a result, it was found that the (E)-exo-olefin isomers showed more potent binding affinity compared with endo-olefin isomers. Among these (E)-exo-olefin isomers, (E)-N-methyl-{1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahyd ro-1H-1 -benzoazepin-5-ylidene}acetamide (14) exhibited the most potent binding affinity and (E)-N-methyl-(1-{4-[2-(4-methylphenyl)benzoylamino]benzoyl}-2,3,4,5- tetrahydro-1H-1-benzoazepin-5-ylidene)acetamide (20) exhibited a high AVP antagonist activity for both V1A and V2 receptors after intravenous administration. Details of the synthesis and pharmacological properties of this series are presented.     

Crystal packing mediates enantioselective ligand recognition at the peripheral site of acetylcholinesterase

Recently, alkylene-linked heterodimers of tacrine (1) and 5-amino-5,6,7,8-tetrahydroquinolinone (2, hupyridone) were shown to exhibit higher acetylcholinesterase (AChE) inhibition than either monomeric 1 or 2. Such inhibitors are potential drug candidates for ameliorating the cognitive decrements in early Alzheimer patients. In an attempt to understand the inhibition mechanism of one such dimer, (RS)-(+/-)-N-9-(1,2,3,4-tetrahydroacridinyl)-N'-5-[5,6,7,8-tetrahydro-2'(1'H)-quinolinonyl]-1,10-diaminodecane [(RS)-(+/-)-3] bisoxalate, the racemate was soaked in trigonal Torpedo californica AChE (TcAChE) crystals, and the X-ray structure of the resulting complex was solved to 2.30 A resolution. Its structure revealed the 1 unit bound to the "anionic" subsite of the active site, near the bottom of the active-site gorge, as seen for the 1/TcAChE complex. Interestingly, only the (R)-enantiomer of the 2 unit was seen in the peripheral "anionic" site (PAS) at the top of the gorge, and was hydrogen-bonded to the side chains of residues belonging to an adjacent, symmetry-related AChE molecule covering the gorge entrance. When the same racemate was soaked in orthorhombic crystals of TcAChE, in which the entrance to the gorge is more exposed, the crystal structure of the corresponding complex revealed no substantial enantiomeric selectivity. This observation suggests that the apparent enantiomeric selectivity of trigonal crystals of TcAChE for (R)-3 is mainly due to crystal packing, resulting in preferential binding of one enantiomeric inhibitor both to its "host" enzyme and to its neighbor in the asymmetric unit, rather than to steric constraints imposed by the geometry of the active-site gorge.     

The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design

Bifunctional derivatives of the alkaloid galanthamine, designed to interact with both the active site of the enzyme acetylcholinesterase (AChE) and its peripheral cation binding site, have been assayed with Torpedo californica AChE (TcAChE), and the three-dimensional structures of their complexes with the enzyme have been solved by X-ray crystallography. Differences were noted between the IC(50) values obtained for TcAChE and those for Electrophorus electricus AChE. These differences are ascribed to sequence differences in one or two residues lining the active-site gorge of the enzyme. The binding of one of the inhibitors disrupts the native conformation of one wall of the gorge, formed by the loop Trp279-Phe290. It is proposed that flexibility of this loop may permit the binding of inhibitors such as galanthamine, which are too bulky to penetrate the narrow neck of the gorge formed by Tyr121 and Phe330 as seen in the crystal structure.     

Design,synthesis, computational and biological evaluation of new benzodiazepines as CNS agents

Two series of new benzodiazepines were synthesized and the target compounds (E1-10 and G1-10) were evaluated for antianxiety and skeletal muscle relaxant activity as CNS agents in albino mice. The chemical structures of the compounds were confirmed on the basis of their TLC, IR, ¹H NMR and ¹³C NMR analysis. In computational studies, the physicochemical similarity of the target compounds was assessed by calculating from a set of physicochemical properties using software programs and test compounds demonstrated moderate physiochemical similarity with respect to diazepam. Log P values of the target compounds indicates good penetration to CNS. Molecular docking studies revealed that the target compounds correctly dock into the binding pocket of the GABA_A receptor, while their bioavailability/drug-likeness was predicted to be acceptable but requires future optimization. The test compounds (E1-10 and G1-10) were screened for antianxiety and skeletal muscle relaxant activity using Elevated plus maze and Rotarod method respectively. Among them, the compounds E10 and G7 showed maximum potency as CNS agents.