Statistical molecular design of peptoid libraries

Statistical experimental design provides an efficient approach for selecting the building blocks to span the structural space and increase the information content in a combinatorial library. A set of renin-inhibitors, hexapeptoids, is used to illustrate the approach. Multivariate quantitative structure-activity relationships (MQSARs) were developed relating renin inhibition to the peptoid sequences variation, parametrized by the z-scales. By using the information from the models, the number of building block sets could be reduced from six to three. Using a statistical molecular design (SMD) reduces the number of compounds from more than 100 000 down to 90. A second SMD was used for comparison, based on less prior knowledge. This gave a reduction from over 2 billion to 120 compounds.     

分子表面随机采样分析用于苯乙基噻唑硫脲衍生物抗艾滋病药物的3D-QSAR研究

采用分子表面随机采样分析(RASMS)对61个苯乙基噻唑硫脲衍生物抗艾滋病药物进行定量构效关系研究.运用多元线性回归(MLR)建模,同时采用内部及外部双重验证的办法对所得模型稳定性能进行深入分析和检验.MLR建模的复相关系数(Rcum)、留一法交互校验复相关系数(QCV)和外部样本校验复相关系数rm(test)分别为0.919、0.856和0.848.结果表明,RASMS能较好表征噻唑硫脲化合物N-(2-苯乙基)-N`-(2-噻唑基)-硫脲(PETT)及其衍生物抗艾滋逆转录酶抑制剂的分子结构信息,且所建模型具有良好稳定性和预测能力,可用于研发新型抗艾滋病药物.     

分子表面随机采样分析用于苯乙基噻唑硫脲衍生物抗艾滋病药物的3D-QSAR研究

摘要：采用分子表面随机采样分析(RASMS)对61个苯乙基噻唑硫脲衍生物抗艾滋病药物进行定量构效关系研究。运用多元线性回归(MLR)建模,同时采用内部及外部双重验证的办法对所得模型稳定性能进行深入分析和检验。MLR建模的复相关系数(Rcum)、留一法交互校验复相关系数(QCV)和外部样本校验复相关系数rm(test)分别为0.919、0.856和0.848。结果表明,RASMS能较好表征噻唑硫脲化合物N-(2-苯乙基)-N`-(2-噻唑基)-硫脲(PETT)及其衍生物抗艾滋逆转录酶抑制剂的分子结构信息,且所建模型具有良好稳定性和预测能力,可用于研发新型抗艾滋病药物。     

Creating molecular diversity from antioxidants in Brazilian propolis. Combination of TOPS-MODE QSAR and virtual structure generation

A QSAR model for antioxidative activity based on the Sub-Structural Molecular Design (TOPS-MODE) approach is developed for a series of compounds present in Brazilian propolis. This approach permitted the structural interpretation of the antioxidative activity of these compounds in terms of bond contributions. By these means we have identified the structural groups and regions that contribute to the antioxidative activity of the cinnamic acid and flavonoid derivatives present in the propolis. These results were then used to identify the positions and substituents to be used in a virtual compound generation experiment. Using this approach a total of 327 compounds were generated from which more than 70 are predicted to be more active than the most powerful antioxidants in the Brazilian propolis. From these 70 compounds less than 20 have been reported in the literature. Consequently, a high proportion of novel compounds with potential antioxidative activity has been identified by the current approach. This contributes to enhance the molecular diversity of the analogues of Brazilian propolis compounds with antioxidative properties.     

Evolutionary computation and multimodal search: A good combination to tackle molecular diversity in the field of peptide design

Summary The awesome degree of structural diversity accessible in peptide design has created a demand for computational resources that can evaluate a multitude of candidate structures. In our specific case, we translate the peptide design problem to an optimization problem, and use evolutionary computation (EC) in tandem with docking to carry out a combinatorial search. However, the use of EC in huge search spaces with different optima may pose certain drawbacks. For example, EC is prone to focus a search in the first good region found. This is a problem not only because of the undesirable and automatic rejection of potentially good search space regions, but also because the found solution may be extremely difficult to synthesize chemically or may even be a false docking positive. In order to avoid rejecting potentially good solutions and to maximize the molecular diversity of the search, we have implemented evolutionary multimodal search techniques, as well as the molecular diversity metric needed by the multimodal algorithms to measure differences between various regions of the search space.     

一种新的自组织聚类网络及其在数据融合目标分类中的应用

介绍了一种新的自组织聚类人工神经网络(DIGNET)模型和网络的非监督学习算法。针对数据融合和目标识别的特点,提出了基于DIGNET的决策层数据融合目标分类方法。利用仿真数据研究了DIGNET和自组织特征映射网络(SOFM)的聚类性能以及基于DIGNET的决策层数据融合结构,实验结果表明DIGNET较SOFM正确分类率高、抗噪能力好;基于DIGNET的决策层数据融合能够有效地实现融合识别。将该数据融合方法应用于前视红外(FLIR)和可见光摄像机目标跟踪系统,结果表明该方法是可行的。     

A computational study on cannabinoid receptors and potent bioactive cannabinoid ligands: homology modeling,docking, de novo drug design and molecular dynamics analysis

When X-ray structure of a ligand-bound receptor is not available, homology models of the protein of interest can be used to obtain the ligand-binding cavities. The steroelectronic properties of these cavities are directly related to the performed molecular model coordinates. Thus, the use of different template structures for homology may result in variation of ligand-binding modes. We have recently reported the MD simulations of a potent CB ligand at bovine rhodopsin-based CB1 and CB2 receptors (Durdagi et al., Bioorg Med Chem 16:7377–7387, 2008). In this present study, a homology modeling study based on the β2-adrenergic receptor for both CB1 and CB2 receptors was performed, and the results were compared with rhodopsin-based models. In addition, the role of membrane bilayers to the adopted conformations of potent AMG3 CB ligand has been analyzed for receptor-free and membrane-associated receptor systems. The performed MD trajectory analysis results have shown that gauche conformations at the terminal segment of the alkyl side chain of AMG3 are not favored in solution. Different adopting dihedral angles defined between aromatic and dithiolane rings at the active sites of the CB1 and CB2 receptors, which are adapted lead to different alkyl side chain orientations and thus, may give clues to the medicinal chemists to synthesize more selective CB ligands. The binding sites of receptors derived by rhodopsin-based models have been regenerated using the β2-adrenergic based template receptors. The re-obtained models confirmed the ligand-binding pockets that were derived based on rhodopsin.     

Role of oxygen functional groups for structure and dynamics of interfacial water on low rank coal surface: a molecular dynamics simulation

Molecular dynamics simulations were employed to study the effects of oxygen functional groups for structure and dynamics properties of interfacial water molecules on the subbituminous coal surface. Because of complex composition and structure, the graphite surface modified by hydroxyl, carboxyl and carbonyl groups was used to represent the surface model of subbituminous coal according to XPS results, and the composing proportion for hydroxyl, carbonyl and carboxyl is 25:3:5. The hydration energy with ?386.28 kJ/mol means that the adsorption process between water and coal surface is spontaneous. Density profiles for oxygen atoms and hydrogen atoms indicate that the coal surface properties affect the structural and dynamic characteristics of the interfacial water molecules. The interfacial water exhibits much more ordering than bulk water. The results of radial distribution functions, mean square displacement and local self-diffusion coefficient for water molecule related to three oxygen moieties confirmed that the water molecules prefer to absorb with carboxylic groups, and adsorption of water molecules at the hydroxyl and carbonyl is similar.     

The dynamic Kingdon trap: A novel design for the storage and crystallization of laser-cooled ions

On the basis of analytical pseudo-potential calculations and extensive numerical simulations it is proved that the dynamic Kingdon trap is a working design for the permanent storage and the crystallization of laser-cooled ions.Dedicated to H. Walther on the occasion of his 60th birthday     

Comparison of reactivity on step and terrace sites of Pd (3 3 2) surface for the dissociative adsorption of hydrogen: A quantum chemical molecular dynamics study

The notion of “active sites” is fundamental to heterogeneous catalysis. However, the exact nature of the active sites, and hence the mechanism by which they act, are still largely a matter of speculation. In this study, we have presented a systematic quantum chemical molecular dynamics (QCMD) calculations for the interaction of hydrogen on different step and terrace sites of the Pd (3 3 2) surface. Finally the dissociative adsorption of hydrogen on step and terrace as well as the influence of surface hydrogen vacancy for the dissociative adsorption of hydrogen has been investigated through QCMD. This is a state-of-the-art method for calculating the interaction of atoms and molecules with metal surfaces. It is found that fully hydrogen covered (saturated) step sites can dissociate hydrogen moderately and that a monovacancy surface is suitable for significant dissociative adsorption of hydrogen. However in terrace site of the surface we have found that dissociation of hydrogen takes place only on Pd sites where the metal atom is not bound to any pre-adsorbed hydrogen atoms. Furthermore, from the molecular dynamics and electronic structure calculations, we identify a number of consequences for the interpretation and modeling of diffusion experiments demonstrating the coverage and directional dependence of atomic hydrogen diffusion on stepped palladium surface.     

A novel method for preparation of 8-hydroxyquinoline functionalized mesoporous silica: Aluminum complexes and photoluminescence studies

8-Hydroxyquinoline (8-HQ) was attached to mesoporous silica by sulfonamide bond formation between 8-hydroxyquinoline-5-sulfonyl chloride (8-HQ-SO₂Cl) and aminopropyl functionalized SBA-15 (designated as SBA-SPS-Q) and then aluminum complexes of 8-HQ was covalently bonded to SBA-SPS-Q using coordinating ability of grafted 8-HQ.The prepared materials were characterized by powder X-ray diffraction (XRD), nitrogen adsorption-desorption, Fourier transform infrared (FT-IR), thermal analysis (TGA-DTA), scanning electron microscopy (SEM), transmission electron microscopy (TEM), elemental analysis and fluorescence spectra. The environmental effects on the emission spectra of grafted 8-HQ and its complexes were studied and discussed in details.     

Ion scattering spectroscopy and scanning tunneling microscopy: A powerful combination for surface structure analysis

Low-energy ion backscattering and scanning tunneling microscopy (STM) have been used in combination to get better insight into the field of surface crystallography. The synergic effectiveness resulting from the complementing character of the two methods has been exemplified at clean NiAl(111) and for oxygen and nitrogen adsorption on Cu(110). The position of the atom cores is accessible by the low-energy noble gas impact collision ion scattering spectroscopy with neutral detection (NICISS). As a technique averaging over a macroscopic area of the sample, NICISS is better suited to supply information on features of completely developed phases, either on clean or adsorbate saturated surfaces. Additional information, on the other hand, can be gained by scanning tunneling microscopy (STM), which as a powerful local probe may be used to image surfaces with atomic resolution and to monitor defects, steps and the growth kinetics of e.g. adsorption-induced phase changes.     

A modified embedded atom method for the corundum and the bixbyite forms of alumina: Bulk and surface studies

We report an atomistic simulation study of alumina in different solid phases: the corundum and the bixbyite ones. By means of the modified embedded atom method, we show that the structural properties of bulk alumina are well reproduced compared with experimental investigations. The equilibrium energy of the bixbyite structure is found to be in the same range as the one of the corundum phase. In addition, the surface energy is also investigated for α-alumina (0 0 0 1) with both aluminum and oxygen terminations.     

A novel Re(I) complex for electroluminescence application: synthesis, theoretical studies, photophysical and electroluminescent properties

In this paper, we report a novel phosphorescent Re(I) complex of Re(CO)₃(ETCP)Br, where ETCP=1-ethyl-2-naphthalen -1-yl-1H-1,3,7,8-tetraaza-cyclopenta[l]phenanthrene, including its photophysical properties, geometric/electronic structures, electrochemical and thermal properties. Experimental data suggest that Re(CO)₃(ETCP)Br is a promising yellow emitter peaking at 540--nm with short excited state lifetime of ∼0.06 μs. Re(I) center localizes in a distorted octahedral field in Re(CO)₃(ETCP)Br and the emissive state of Re(CO)₃(ETCP)Br has metal-to-ligand-charge-transfer character, leading to the room-temperature phosphorescence. Further analysis reveals that Re(CO)₃(ETCP)Br has HOMO and LUMO energy levels at −6.03 V and −3.56 V, respectively, as well as its high thermal decomposition temperature of 377 °C. Using Re(CO)₃(ETCP)Br as a dopant, an electroluminescence peaking at 565-nm is realized, with a maximum luminance of 5900 cd/m² and a maximum current efficiency of 11.3 cd/A.     

3D H2BC: A novel experiment for small-molecule and biomolecular NMR at natural isotopic abundance

3D H2BC is introduced for heteronuclear assignment on natural abundance samples even for biomolecules up to at least 10 kDa in low millimolar concentrations as an overnight experiment using the latest generation of cryogenically cooled probes. The short pulse sequence duration of H2BC is maintained in the 3D version due to multiple use of the constant-time delay. Applications ranging from a small lipid to a non-recombinant protein demonstrate the merits of 3D H2BC and the ease of obtaining assignments in chains of protonated carbons.     

Weak and strong hydrogen bonds conducting the supramolecular framework of 1-butyl-3-(1-naphthoyl)thiourea: crystal structure,vibrational studies,DFT methods,Pixel energies and Hirshfeld surface analysis

A detailed structural and spectroscopic study of a new thiourea derivative 1-butyl-3-(1-naphthoyl)thiourea (1) is presented with the assistance of theoretical calculations. The X-ray diffraction structure analysis reveals a planar carbonylthiourea group, favoured by intra-molecular NH···O bond. The compound is arranged in the lattice as NH···O and NH···S bonded polymeric ribbons, that extend along the crystal b-axis. Molecular pairs involving N–H···S hydrogen bonds are a dominant contribution to packing stabilisation coming from coulombic component. Hirshfeld surfaces and two-dimensional-fingerprint plots show different intermolecular contacts and its relative contributions to total surface in each compound. The AIM approach shows the nature and strength of the strong and weak intramolecular interactions and the solvent effect, while NBO analysis reveals that the sulphur atom is responsible for the higher hyperconjugative stabilising energy.     

A novel electron scattering apparatus combining a laser photoelectron source and a triply differentially pumped supersonic beam target: characterization and results for the resonance

A novel electron scattering apparatus for high resolution studies of angle-differential elastic and inelastic electron scattering from atoms and molecules in the gas phase is described and its performance characterized. It combines a laser photoelectron source, a triply differentially pumped collimated supersonic beam target (half angle 0.015 rad, background to beam density ratio < 0.01), and several electron multipliers for simultaneous detection of elastically scattered electrons and metastable atoms (or molecules) due to inelastic scattering. In detailed test measurements of the yield for the production of metastable He^*(2³S₁) atoms around its threshold, the dependence of the overall energy width on various experimental parameters has been investigated. So far a resolution down to 7 meV (FWHM) has been obtained. Under such conditions we have investigated the profile of the He^- (1 s 2 s ^{2 2} S _1/2 ) resonance at the scattering angles 22 ^° , 45 ^° , and 90 ^° . From a consistent fit of the measured profiles by resonant scattering theory we determine a new value for the resonance energy ( E _r = 19.365(1) eV) and an accurate resonance width ( Γ = 11.2(5) meV). These results are consistent with the previously recommended values. Received 23 July 2002 Published online 29 October 2002 RID="a" ID="a"e-mail: hotop@physik.uni-kl.de RID="b" ID="b"Permanent address: Department of Physics and Astronomy, Drake University, Des Moines, IA 50311, USA.