TGSA: A molecular superposition program based on topo‐geometrical considerations

In this article, a new molecular alignment procedure to provide general‐purpose, fast, automatic, and user‐intuitive three‐dimensional molecular alignments is presented. This procedure, called Topo‐Geometrical Superposition Approach (TGSA), is only based on comparisons of atom types and interatomic distances; hence, the procedure can handle large molecular sets within affordable computational costs. The method is able to accurately align 3D structures using the common molecular substructures, as inferred by the bonding pattern (atom correspondences), where present. The algorithm has been implemented into a program named TGSA99, and it has been tested over eight different molecular sets: flavilium salts, amino acids, indole derivatives, AZT, steroids, anilide derivatives, poly‐aromatic‐hydrocarbons, and inhibitors of thrombine. The TGSA algorithm performance is evaluated by means of computational time, number of superposed atoms, and index of fit between the compared structures. © 2000 John Wiley & Sons, Inc. J Comput Chem 22: 255–263, 2001     

Quantum similarity superposition algorithm (QSSA): a consistent scheme for molecular alignment and molecular similarity based on quantum chemistry

The use of the molecular quantum similarity overlap measure for molecular alignment is investigated. A new algorithm is presented, the quantum similarity superposition algorithm (QSSA), expressing the relative positions of two molecules in terms of mutual translation in three Cartesian directions and three Euler angles. The quantum similarity overlap is then used to optimize the mutual positions of the molecules. A comparison is made with TGSA, a topogeometrical approach, and the influence of differences on molecular clustering is discussed.     

Theoretical model for the polarization molecular and Hückel treatment of PhosphoCyclopentadiene in an external electric field: Hirschfeld study

In this study we relate the Hückel method and molecular polarization of PhosphoCyclopentadiene (P-cyclopentadiene) with respect to the Cyclopentadienyl, and its consequent separation of charges of particular set of conjugated diene systems. The Hückel method and Molecular Polarization of P-cyclopentadiene is expressed as a function of the induced polarizability of Cyclopentadienylin an external electric field, presenting a technique to express the molecular polarizabilities and Hückel method of diene systems as a function of another in an external electric field, using local quantum similarity index (LQSI) based on the Hirschfeld partitioning in the framework of conceptual density functional theory, this index was introduced in the molecular polarization of cyclopentadienyl in an external electric field and in the secular determinant of the Hückel method applied to the Cyclopentadienylin order to express the molecular polarization and Hückel method as a function of P-cyclopentadiene using six local similarity index: Overlap, Overlap-Interaction, Coulomb, Coulomb-Interaction, Overlap-Euclidian distance and Coulomb-Euclidian distance.The topo-geometrical superposition approach (TGSA) was used as method of alignment, which allows us to obtain high results in the proposed LQSIs, this method to be a straightforward procedure to cope with the problem of relative orientation of the molecules when evaluating, developing a new technique that will allow us to study structural systems that differ in one atom in its structure, and proposing methodologies for future studies on a much broader range of systems in which the Hückel method and molecular polarization of two species that differ only in one atom in its structure can be approximated in this way.     

Ordered structures in proton conducting membranes from supramolecular liquid crystal polymers

Highly sulfonated forms of poly(p-phenylene terephthalamide) (PPTA) have been prepared in three different molecular configurations; sulfonated diamine form (S-PPTA), sulfonated terephthalic acid form (S-invert-PPTA), and the bi-sulfonated form (S2-PPTA). All three polymers are water soluble to a certain degree and films were cast from solution for S-PPTA and S-invert-PPTA. S-PPTA films absorb less water than S-invert-PPTA (under controlled humidity conditions) and consequently, the conductivity for this polymer is also slightly lower. Although the conductivities are comparable to Nafion (of the order of 10(-2) to 10(-1) Scm(-1)), proton mobility is more restricted. X-ray diffraction showed that the rigid molecules are aligned in opposite directions for the two polymer films, being homeotropic in S-PPTA films and planar for S-invert-PPTA. SEM analysis demonstrated layering in the same direction as the alignment of the polymer chains. The variation in the polymer alignment is most likely the result of the differences in the solution properties and the film forming process. It is possible, however, that this alignment could be exploited to enhance proton transport and thus these films are of interest for fuel cell membranes.     

Refinement of local and long-range structural order in theophylline-binding RNA using (13)C-(1)H residual dipolar couplings and restrained molecular dynamics.

13C-(1)H residual dipolar couplings (RDC) have been measured for the bases and sugars in the theophylline-binding RNA aptamer, dissolved in filamentous phage medium, and used to investigate the long-range structural and dynamic behavior of the molecule in the solution state. The orientation dependent RDC provide additional restraints to further refine the overall structure of the RNA-theophylline complex, whose long-range order was poorly defined in the NOE-based structural ensemble. Structure refinement using RDC normally assumes that molecular alignment can be characterized by a single tensor and that the molecule is essentially rigid. To address the validity of this assumption for the complex of interest, we have analyzed distinct domains of the RNA molecule separately, so that local structure and alignment tensors experienced by each region are independently determined. Alignment tensors for the stem regions of the molecule were allowed to float freely during a restrained molecular dynamics structure refinement protocol and found to converge to similar magnitudes. During the second stage of the calculation, a single alignment tensor was thus applied for the whole molecule and an average molecular conformation satisfying all experimental data was determined. Semirigid-body molecular dynamics calculations were used to reorient the refined helical regions to a relative orientation consistent with this alignment tensor, allowing determination of the global conformation of the molecule. Simultaneously, the local structure of the theophylline-binding core of the molecule was refined under the influence of this common tensor. The final ensemble has an average pairwise root mean square deviation of 1.50 +/- 0.19 A taken over all heavy atoms, compared to 3.5 +/- 1.1 A for the ensemble determined without residual dipolar coupling. This study illustrates the importance of considering both the local and long-range nature of RDC when applying these restraints to structure refinements of nucleic acids.     

4',5'-Dichloro-2',7'-dimethoxy-5(6)-carboxyfluorescein (JOE): synthesis and spectral properties of oligonucleotide conjugates

A convenient procedure for the preparation of the fluorescent dye 4',5'-dichloro-2',7'-dimethoxy-5(6)-carboxyfluorescein (JOE) is reported; the overall yield achieved starting from isovanillin is 10 times higher (40% vs 4%) compared to the known procedure. Isomers (5- and 6-) are easily chromatographically separable as pentafluorophenyl esters of 3',6'-O-bis(cyclohexylcarbonyl) derivatives. Four non-nucleoside JOE phosphoramidites based on 5- and 6-isomers and flexible 6-aminohexanol (AH) or rigid 4-trans-aminocyclohexanol (ACH) linkers have been prepared and used for oligonucleotide labeling. Spectral and photophysical properties of 5'-JOE-modified oligonucleotides have been studied. Fluorescence quantum yield of the dye correlates with the nature of the linker (rigid vs flexible) and with the presence of dG nucleosides in close proximity to a JOE residue.     

Design,synthesis, pharmacological evaluation and in silico ADMET prediction of novel substituted benzimidazole derivatives as angiotensin II–AT1 receptor antagonists based on predictive 3D QSAR models

In this study we designed novel substituted benzimidazole derivatives and predicted their absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, based on a predictive 3D QSAR study on 132 substituted benzimidazoles as AngII–AT₁ receptor antagonists. The two best predicted compounds were synthesized and evaluated for AngII–AT₁ receptor antagonism. Three different alignment tools for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used. The best 3D QSAR models were obtained using the rigid body (Distill) alignment method. CoMFA and CoMSIA models were found to be statistically significant with leave-one-out correlation coefficients (q²) of 0.630 and 0.623, respectively, cross-validated coefficients (r²_cv) of 0.651 and 0.630, respectively, and conventional coefficients of determination (r²) of 0.848 and 0.843, respectively. 3D QSAR models were validated using a test set of 24 compounds, giving satisfactory predicted results (r²_pred) of 0.727 and 0.689 for the CoMFA and CoMSIA models, respectively. We have identified some key features in substituted benzimidazole derivatives, such as lipophilicity and H-bonding at the 2- and 5-positions of the benzimidazole nucleus, respectively, for AT₁ receptor antagonistic activity. We designed 20 novel substituted benzimidazole derivatives and predicted their activity. In silico ADMET properties were also predicted for these designed molecules. Finally, the compounds with best predicted activity were synthesized and evaluated for in vitro angiotensin II–AT₁ receptor antagonism.     

Dipole Moments and Intermolecular Association of Some Carbonyl Compounds in Nonpolar Solvents

The aggregation of some aldehydes in nonpolar solvents was investigated using the static dielectric method. The molecular association of acetone and two of its derivatives (acetophenone and benzophenone) in cyclohexane solvent were also investigated by this method. Analysis of the static dielectric data for solution of these materials indicated a high molecular association. It was found that benzaldehyde and its derivatives have a strong tendency for antiparallel molecular association, whereas acetone and its derivatives have a tendency for parallel alignment. The experimental results show that there is a sensitive relationship between the molecular association and molecular structure of these materials. The influence of solvent on the molecular association of the solute molecules was studied and compared.     

Improved 3D-QSAR prediction by multiple-conformational alignment: A case study on PTP1B inhibitors

Three-dimension quantitative structure activity relationship (3D-QSAR) was one of the major statistical techniques to investigate the correlation of biological activity with structural properties of candidate molecules, and the accuracy of statistic greatly depended on molecular alignment methodology. Exhaustive conformational search and successful conformational superposition could extremely improve the predictive accuracy of QSAR modeling. In this work, we proposed a solution to optimize QSAR prediction by multiple-conformational alignment methods, with a set of 40 flexible PTP1B inhibitors as case study. Three different molecular alignment methods were used for the development of 3D-QSAR models listed as following: (1) docking-based alignment (DBA); (2) pharmacophore-based alignment (PBA) and (3) co-crystallized conformer-based alignment (CCBA). Among these three alignments, it was indicated that the CCBA was the best and the fastest strategy in 3D-QSAR development, with the square correlation coefficient (r²) and cross-validated squared correlation coefficient (q²) of comparative molecular field analysis (CoMFA) were 0.992 and 0.694; the r² and q² of comparative molecular similarity indices analysis (CoMSIA) were 0.972 and 0.603, respectively. The alignment methodologies used here not only generated a robust QSAR model with useful molecular field contour maps for designing novel PTP1B inhibitors, but also provided a solution for constructing accurate 3D-QSAR model for various disease targets. Undoubtedly, such attempt in QSAR analysis would greatly help us to understand essential structural features of inhibitors required by its target, and so as to discover more promising chemical derivatives.     

2,4,6-三萘基-1,3,5-三嗪的合成与光谱行为

本文通过Suzuki偶联反应高效合成了两种三萘基三嗪化合物,即2,4,6-三(1-萘基)-1,3,5-三嗪(T1NT)和2,4,6-三(2-萘基)-1,3,5-三嗪(T2NT). 考察了介质的极性、温度以及THF-H₂O二元溶剂体系中的溶解性等因素对它们吸收和发射光谱行为的影响.研究发现, 由于T1NT比T2NT具有更好的分子平面性,其激发态下分子内电荷转移的程度较大,导致其在溶液中吸收光谱、发射光谱比T2NT呈现显著红移.冻结态下,分子平面性较差的T2NT显示出较短波长的发光.     

Analysis of estrogens in river water and effluents using solid-phase extraction and gas chromatography-negative chemical ionisation mass spectrometry of the pentafluorobenzoyl derivatives

A procedure was developed for the analysis of estrogens in environmental water and effluents. Samples were extracted by passing through polymer-impregnated solid-phase extraction discs or C18 cartridges, followed by gas chromatography-negative chemical ionisation mass spectrometry of the pentafluorobenzoyl derivatives. The derivatives were stable and gave diagnostic negative molecular ions as the base peak for each of the major estrogens studied. The absolute recovery of estrogens spiked into clean groundwater using the disc procedure was 84-116% at the 10 ng l(-1) level (calculation not based on use of internal standards). Using doubly deuterated estradiol as internal standard added prior to extraction, the % relative standard deviation of estrogen extraction and analysis in spiked groundwater at the 10 ng(-1) level was 2.6-9.8%. Detection limits were 0.2 ng l(-1) or below for the major estrogens, based on a 2.5 litre sample. The most abundant estrogen was estrone, with concentrations over the range 6.4-29 ng l(-1) in effluents, and 0.2 to 17 ng l(-1) in water from the River Thames.     

Langmuir monolayers of the long-chain alkyl derivatives of a nucleoside analogue and the formation of self-assembled nanoparticles

The long-chain alkyl derivatives of a nucleoside analogue-acyclovir were prepared in the paper. One is stearyl-glycero-succinyl-acyclovir (SGSA) with a single 18-carbon length (C18) alkyl chain. Another is dioctadecyl-aspartate-succinyl-acyclovir (DASA) with double C18 alkyl chains. They were prepared by the esterification of succinyl-acyclovir with the lipids, and sodium salts of them were also prepared. Guanine moieties and alkyl moieties bring the derivatives intermolecular hydrogen bonding and hydrophobic interaction in water separately. The forces are influenced by the number of alkyl chains and the charged state, and determine the solubility and the self-assembly behavior of the derivatives. The double alkyl-chain derivatives (DASA and DASA-Na) formed rigid Langmuir monolayers on air/water surface, while the single alkyl chain derivatives (SGSA and SGSA-Na) did not. However, cholesterol (Chol) could assist SGSA to form rigid monolayers through inserting into the alkyl chains of SGSA to mimic the second alkyl chain. SGSA self-aggregates in water were prepared by the injection method with tetrahydrofuran as solvent. Cuboid-like shape and nanoscale size demonstrated that SGSA self-aggregates were self-assembled nanoparticles. Shape, particle size, zeta potential and phase transition of the nanoparticles were characterized. And they showed an average size of 83.2 nm, a negative surface charge of -31.3-mV zeta potential and a gel-liquid crystalline phase transition of 50.38 degrees C. The formation mechanism of self-assembled nanoparticles was analyzed. Hydrophobic interaction of alkyl chains improves SGSA molecules to form bilayers, and then cuboid-like nanoparticles were obtained by layer-by-layer aggregation based on inter-bilayers hydrogen bonding. However, the charged guanine moieties make SGSA-Na lose the function of hydrogen bonding so that SGSA-Na only forms vesicles in water based on hydrophobic interaction. Strong hydrophobicity and wide-open rigid double alkyl chains of DASA and DASA-Na restrict self-assembly in water media, and no homogeneous suspensions were obtained. Therefore, the molecular self-assembly behavior of the long-chain alkyl derivatives of nucleoside analogues on water surface or in water media is determined by the number of alkyl chains and the charged state.     

Characterising and optimising impulsive molecular alignment in mixed gas samples

Laser induced impulsive molecular alignment has been fully characterized in linear molecules by matching numerical simulations and experimental data of the corresponding rotational wavepacket in the frequency domain. A rigorous procedure for an accurate matching between simulation and experimental data is presented for the first time, making this a versatile technique for experiments where the molecular axis distribution is not directly accessible. Seeding small molecules in Ar as a carrier gas has then been employed to assist cooling and we systematically retrieve the molecule's rotational temperature and alignment distribution for different mixing ratios. For a total backing pressure of 2 bar it was found that seeding 10% N(2) in Ar results in the best cooling. Compared to pure N(2) the rotational temperature was reduced from 24 ± 2 K down to 9 ± 2 K. This leads to an improvement of the peak alignment distribution from = 0.60 to = 0.71. For the same mixing ratio CO(2) was cooled from 34 ± 3 K to 9 ± 1 K improving the alignment distribution from 0.48 to 0.64. In O(2) a cooling from 58 ± 2 K to 37 ± 4 K was observed, corresponding to an alignment distribution improvement from 0.49 to 0.58. The results demonstrate the wide applicability of the characterisation procedure and of seeded supersonic beams to optimise impulsive alignment of small molecules.     

Simulation studies of dipole correlation in the isotropic liquid phase

The Kirkwood correlation factor g₁ determines the preference for local parallel or antiparallel dipole association in the isotropic phase. Calamitic mesogens with longitudinal dipole moments and Kirkwood factors greater than 1 have an enhanced effective dipole moment along the molecular long axis. This leads to higher values of Δ? in the nematic phase. This paper describes state-of-the-art molecular dynamics simulations of two calamitic mesogens 4-(trans-4-n-pentylcyclohexyl)benzonitrile (PCH5) and 4-(trans-4-n-pentylcyclohexyl)chlorobenzene (PCH5-Cl) in the isotropic liquid phase using an all-atom force field and taking long range electrostatics into account using an Ewald summation. Using this methodology, PCH5 is seen to prefer antiparallel dipole alignment with a negative g₁ and PCH5-Cl is seen to prefer parallel dipole alignment with a positive g₁; this is in accordance with experimental dielectric measurements. Analysis of the molecular dynamics trajectories allows an assessment of why these molecules behave differently.     

Measurement of the field-free alignment of diatomic molecules

An apparatus was constructed to experimentally quantify the field-free alignment of diatomic molecules irradiated by strong femtosecond laser pulses. In this apparatus, both homodyne and pure heterodyne detections were realized. The alignment signal is proportional to [ - 1/3](2) for homodyne detection and ( - 1/3) for pure heterodyne detection, where theta is the polar angle between the molecular axis and the laser polarization direction. Fourier transform spectra of the homodyne signal and the pure heterodyne signal were also studied. By comparing the alignment signal and its Fourier transform spectrum with the numerical calculation of the time-dependent Schr?dinger equation, we demonstrated that the pure heterodyne signal directly reproduced the alignment parameter , and its Fourier transform spectrum provided information regarding the populations of different J states in the rotational wavepacket.     

pi-topology and spin alignment utilizing the excited molecular field: observation of the excited high-spin quartet (S = 3/2) and quintet (S = 2) states on purely organic pi-conjugated spin systems.

As a model system for the photoinduced/photoswitched spin alignment in a purely organic pi-conjugated spin system, 9-[4-(4,4,5,5-tetramethyl-1-yloxyimidazolin-2-yl)phenyl]anthracene (1a), 9-[3-(4,4,5,5-tetramethyl-1-yloxyimidazolin-2-yl)phenyl]anthracene (1b), 9,10-bis[4-(4,4,5,5-tetramethyl-1-yloxyimidazolin-2-yl)phenyl]anthracene (2a), and 9,10-bis[3-(4,4,5,5-tetramethyl-1-yloxyimidazolin-2-yl)phenyl]anthracene (2b) were designed and synthesized. In these spin systems, 9-phenylanthracene and 9,10-diphenylanthracene were chosen as photo spin couplers and iminonitroxide was chosen as a dangling stable radical. Time-resolved electron spin resonance (TRESR) spectra of the first excited states with resolved fine-structure splittings were observed for 1a and 2a in an EPA or a 2-MTHF rigid glass matrix. Using the spectral simulation based on the eigenfield method, the observed TRESR spectra for 1a and 2a were unambiguously assigned as an excited quartet (S = 3/2) spin state (Q) and an excited quintet (S = 2) spin state (Qu), respectively. The g value and fine-structure splitting for the quartet state of 1a were determined to be g(Q) = 2.0043, D(Q) = 0.0235 cm(-1), and E(Q) = 0.0 cm(-1). The relative populations (polarization) of each M(S)() sublevel in Q were determined to be P(+1/2') = P(-1/2') = 0.5 and P(+3/2') = P(-3/2') = 0.0 with an increasing order of energy in zero magnetic field. The spin Hamiltonian parameters for Qu are g = 2.0043, D = 0.0130 cm(-1), and E = 0.0 cm(-1), and the relative populations in Qu were determined to be P(0') = 0.30, P(-1') = P(+1') = 0.35 and P(-2') = P(+2') = 0.0. These are the first observations of a photoexcited quartet and a quintet high-spin state in pi-conjugated triplet-radical pair systems. In contrast high-spin excited states were not observed for 1b and 2b, the pi-topological isomers of 1a and 2a, showing the role of pi-topology in the spin alignment of the excited states. Since a weak antiferromagnetic exchange interaction was observed in the ground state of 2a, the clear detection of the excited quintet high-spin state shows that the effective exchange coupling between the two dangling radicals through the diphenylanthracene spin coupler has been changed from antiferromagnetic to ferromagnetic upon photoexcitation. Thus, a photoinduced spin alignment utilizing the excited triplet molecular field was realized for the first time in the purely organic pi-conjugated spin system. Furthermore, the mechanism for the generation of dynamic electron spin polarization was investigated for the observed quartet and quintet states, and a plausible mechanism of the enhanced selective intersystem crossing was proposed. Ab initio molecular orbital calculations based on density functional theory were carried out to determine the electronic structures of the excited high-spin states and to understand the mechanism of the spin alignment utilizing the excited molecular field. The role of the spin delocalization and the spin polarization mechanisms were revealed on the photoexcited state.     

两种组氨酸酰胺衍生物的合成及其与人血清白蛋白的结合

L-组氨酸对生物有机体有着良好的亲和能力,通过修饰其化学结构以期寻找药理活性和生物利用度高的衍生物。本文将L-组氨酸分别与反式肉桂酸和对甲氧基肉桂酸反应,合成了两种组氨酸酰胺类衍生物,利用傅里叶变换红外光谱、质谱、氢谱/碳谱核磁共振谱进行了结构表征。采用分子操作环境(MOE)软件分子对接技术、荧光光谱法、同步荧光光谱法(SFS)、紫外-可见光谱法(UV-Vis),共同研究了两种衍生物分别和人血清白蛋白(HSA)相结合的机理。MOE对接结果显示,这两种衍生物与HSA的模拟结合能分别为-13.82和-16.25 kcal/mol,主要是通过范德华力和疏水作用结合在HSA亚结构域ⅡA(即siteⅠ)的疏水腔内。荧光猝灭数据表明,衍生物与HSA相互作用并形成了新的基态配合物,荧光猝灭过程为静态猝灭;不同温度(300、305和310 K)下衍生物与HSA相互作用的结合常数分别为1.773×104、6.354×10~3、1.260×10~3和5.314×10~4、4.614×10~3、1.420×10~3;由热力学参数得到衍生物与HSA的结合过程是由范德华力驱动;SFS表明,衍生物使得HSA的二级结构发生了变化。结合UV-Vis的结果可以确定,在体外生理条件下,组氨酸酰胺类衍生物均可以通过范德华力与HSA结合,并对HSA内源荧光产生静态猝灭及构象影响,这与分子对接结果一致,从而为组氨酸酰胺类衍生物药物的进一步开发提供了参考。