Use of metal/metal oxide spherical cluster and hydroxyl metal coordination complex for descriptor calculation in development of nanoparticle cytotoxicity classification model.

Computational approaches have been suggested as an informative tool for risk assessment of nanomaterials. Nano (quantitative) structure-activity relationship, nano-(Q)SAR, models have been developed to predict toxicity of metal oxide (MOx) nanoparticles (NPs); however, the packing structure and cluster of nanoparticle have been included for the descriptor calculation in only two studies. This study proposed spherical cluster and hydroxyl metal coordination complex to calculate descriptors for development of nanoparticle cytotoxicity classification model. The model cluster was generated from metal (M) or MOx crystal structure to calculate physicochemical properties of M/MOx NPs and the hydroxyl metal coordination complex was used to calculate the properties of the metal cation in an aqueous environment. Data were collected for 2 M and 19 MOx NPs in human bronchial epithelial cell lines and murine myeloid cell lines at 100 µg/ml after 24 hours exposure. The model was developed with scaled HOMO energy of the model cluster and polarizability of the hydroxyl metal coordination complex, as reactivity of the particles and the cations explained cause of cytotoxic action by M/MOx NPs. As the developed model achieved 90.31% accuracy, the classification model in this work can be used for virtual screening of toxic action of M/MOx NPs.

CXXC5 is a negative-feedback regulator of the Wnt/ß-catenin pathway involved in osteoblast differentiation.

The positive roles of the Wnt/ß-catenin pathway in osteoblast differentiation and bone mineral density (BMD) maintenance have been clearly demonstrated in both animal experiments and clinical investigations. CXXC finger protein 5 (CXXC5), a recently identified negative regulator of the Wnt/ß-catenin pathway, showed altered cellular localization and function, which were dependent on the cell type in previous studies. However, the in vivo function of CXXC5 has not been clearly investigated yet. Here, we characterized CXXC5 as a negative regulator of osteoblast differentiation and bone formation. Deficiency of CXXC5 resulted in elevated BMD in mice without any severe gross developmental abnormalities. CXXC5 exerted a negative-feedback effect on the Wnt/ß-catenin pathway via Wnt-dependent binding to Dishevelled (Dvl) during osteoblast differentiation. Suppression of the Dvl-CXXC5 interaction using a competitor peptide resulted in the activation of the Wnt/ß-catenin pathway and osteoblast differentiation, and accelerated thickness growth of ex vivo-cultured calvariae. Overall, CXXC5 is a negative-feedback regulator induced by Wnt/ß-catenin signaling that inhibits osteoblast differentiation and bone formation via interaction with Dvl.

An empirical model for gas phase acidity and basicity estimation.

Gas phase acidity and basicity estimation models have been developed for acidic and basic functional groups of amino acid side-chains and also for a number of small organic molecules. The acidic functional groups include aliphatic and aromatic alcohol, and aliphatic and aromatic carboxylic acid, and the basic functional groups include aliphatic, aromatic and hetero-aromatic amines, and also pyridino-, pyrazolo- and imidazolo-groupings. The models are described in terms of a linear combination of descriptors that highly influence reactivity at the reaction centres of the functional groups. In order to describe the chemical environments of the deprotonating and protonating sites, atomic descriptors such as the effective atomic electronegativity and effective atomic polarizability of the atoms in the reaction field and the electrostatic potentials at the reaction sites have been introduced. The coefficient of determination (r(2)) of each model is above 0.8, apart from the imidazole model. The models are readily applicable, ranging from simple organic molecules to proteins.

PXR ligand classification model with SFED-weighted WHIM and CoMMA descriptors.

Understanding which type of endogenous and exogenous compounds serve as agonists for the nuclear pregnane X receptor (PXR) would be valuable for drug discovery and development, because PXR regulates a large number of genes related to xenobiotic metabolism. Although several models have been proposed to classify human PXR activators and non-activators, models with better predictability are necessary for practical purposes in drug discovery. Grid-weighted holistic invariant molecular (G-WHIM) and comparative molecular moment analysis (G-CoMMA) type 3D descriptors that contain information about the solvation free energy of target molecules were developed. With these descriptors, prediction models built using decision tree (DT)-, support vector machine (SVM)-, and Kohonen neural network (KNN)-based models exhibited better predictability than previously proposed models. Solvation free energy density-weighted G-WHIM and G-CoMMA descriptors reveal new insights into PXR ligand classification, and incorporation with machine learning methods (DT, SVM, KNN) exhibits promising results, especially SVM and KNN. SVM- and KNN-based models exhibit accuracy around 0.90, and DT-based models exhibit accuracy around 0.8 for both the training and test sets.

yaInChI: modified InChI string scheme for line notation of chemical structures.

A modified InChI (International Chemical Identifier) string scheme, yaInChI (yet another InChI), is suggested as a method for including the structural information of a given molecule, making it straightforward and more easily readable. The yaInChI theme is applicable for checking the structural identity with higher sensitivity and generating three-dimensional (3-D) structures from the one-dimensional (1-D) string with less ambiguity than the general InChI method. The modifications to yaInChI provide non-rotatable single bonds, stereochemistry of organometallic compounds, allene and cumulene, and parity of atoms with a lone pair. Additionally, yaInChI better preserves the original information of the given input file (SDF) using the protonation information, hydrogen count +1, and original bond type, which are not considered or restrictively considered in InChI and SMILES. When yaInChI is used to perform a duplication check on a 3D chemical structure database, Ligand.Info, it shows more discriminating power than InChI. The structural information provided by yaInChI is in a compact format, making it a promising solution for handling large chemical structure databases.

Backbone dynamics for the wild type and a double H52R/T56W mutant of the vnd/NK-2 homeodomain from Drosophila melanogaster.

The (15)N relaxation behavior and heteronuclear Overhauser effect data for the wild type and an H52R/T56W double mutant protein that encompasses the vnd/NK-2 homeodomain from Drosophila melanogaster were used to characterize and describe the protein backbone dynamics. This investigation, which includes a description of a model structure for the H52R/T56W double mutant vnd/NK-2 homeodomain, was carried out for the two proteins in both the free and DNA-bound states. The double residue replacement at positions 52 and 56 within the DNA recognition helix of vnd/NK-2 has been shown to lead to a significant secondary structural modification resulting in an increase in the length of the recognition helix for the unbound protein. These structural changes are accompanied by corresponding changes in the T(1) and T(1)(rho) relaxation times as well as in the heteronuclear Overhauser effect (XNOE) values that show that the structural stability of the protein is enhanced by the two residue replacements. The values of the rotational anisotropy, D(parallel)/D(perpendicular), derived from analysis of the (15)N T(1) and T(1)(rho) relaxation values are small (1.189 for the unbound homeodomain and 1.110 for the bound homeodomain; both analyzed as prolate ellipsoids of revolution). A comparison of the T(2) values of the wild type and double mutant homeodomain reveals the presence of a low-frequency exchange contribution for the wild type analogue. These relaxation studies show that the motional behavior of the protein primarily reflects the tertiary structure and stability of the homeodomain backbone as well as the respective changes induced upon site-directed residue replacement or DNA binding.

Molecular engineering. 8. Kinetic and conformational studies of resorcin [4]arene-based C4 tetraoxatetrathiahemicarceplexes: carceroisomerism and twistomerism.

New C(4v) tetraoxatetrathiahemicarcerands and their six hemicarceplexes containing DMF, DMA, DMSO, or NMP were synthesized and characterized. Their conformations, kinetic properties, carceroisomerism, and twistomerism were studied by VT, 2D COSY, NOESY, and ROESY (1)H NMR experiments. The decomplexation rates of DMF or DMA were very slow with high activation energy barriers (73 and 104 kJ mol(-1), respectively) and the complexed guests feel more constriction than their free liquid state. The largest isomerization energy barrier of carceroisomers was 15.4 kcal mol(-1), and the isomerization energy barriers of twistomers are significantly larger than those of carceroisomers.

Design and synthesis of highly potent fumagillin analogues from homology modeling for a human MetAP-2.

New fumagillin analogues were designed through structure-based molecular modeling with a human methionine aminopeptidase-2. Among the fumagillin analogues, cinnamic acid ester derivative CKD-731 showed 1000-fold more potent proliferation inhibitory activity on endothelial cell than TNP-470.

Development of three-dimensional descriptors represented by tensors: free energy of hydration density tensor.

In order to describe the degree of interaction of a molecule with its environments by descriptors, several three-dimensional descriptors have been proposed. With the physical properties calculated around a molecule, scalar, vector, and tensor (zeroth, first, and second moments) of the physical properties were calculated and were used as descriptors for calculating the similarity index between the molecules. The tensors contain the information on the spatial distribution of those physical properties around the molecule. Hydration Free Energy Density (HFED) proposed by No et al. was used to calculate HFED tensor. The descriptors were used for the similarity index calculations between substituted benzenes and between lead compounds of HIV-1 protease inhibitors. The substituted benzenes are grouped according to the similarity indices. The grouping seems reasonable from the viewpoint of a chemical sense. The lead fragments of the HIV-1 protease inhibitors have a high similarity among themselves though their chemical formulas are not very similar, the lead fragments are diverse. Although the chemical formulas are diverse, the spatial distribution of the physical properties around the molecules is similar. The descriptors have high discriminating power in the similarity calculation between the molecules.

Description of hydration free energy density as a function of molecular physical properties.

A method to calculate the solvation free energy density (SFED) at any point in the cavity surface or solvent volume surrounding a solute is proposed. In the special case in which the solvent is water, the SFED is referred to as the hydration free energy density (HFED). The HFED is described as a function of some physical properties of the molecules. These properties are represented by simple basis functions. The hydration free energy of a solute was obtained by integrating the HFED over the solvent volume surrounding the solute, using a grid model. Of 34 basis functions that were introduced to describe the HFED, only six contribute significantly to the HFED. These functions are representations of the surface area and volume of the solute, of the polarization and dispersion of the solute, and of two types of electrostatic interactions between the solute and its environment. The HFED is described as a linear combination of these basis functions, evaluated by summing the interaction energy between each atom of the solute with a grid point in the solvent, where each grid point is a representation of a finite volume of the solvent. The linear combination coefficients were determined by minimizing the error between the calculated and experimental hydration free energies of 81 neutral organic molecules that have a variety of functional groups. The calculated hydration free energies agree well with the experimental results. The hydration free energy of any other solute molecule can then be calculated by summing the product of the linear combination coefficients and the basis functions for the solute.

Bis azo dyes--studies on the mechanism of complex formation with IgG modulated by heating or antigen binding.

The mechanism of binding of azo dyes (bis azo) to immunoglobulin G of altered conformation, induced by heating or interaction with antigen was analysed in this work. Azo dyes: Congo Red, Evans Blue and Trypan Blue were selected for these studies. The molecules of Congo Red and Evans Blue associate readily in water and exist as polymolecular micellar species of liquid crystalline organization. Such organization of molecules appeared necessary for these dyes to interact with antibodies and to affect the formation of immune complex. It was proved by studying the properties of isomeric dyes Evans Blue and Trypan Blue, whose ability to form polymolecular conglomerates in water differs, being high for Evans Blue and low for Trypan Blue. The dyes seem to influence the formation of the immune complex generally by interacting with individual immunoglobulin molecules. The rate of exchange of dye molecules in conglomerate bound to protein varies and is the lowest for the portion of molecules which are engaged directly in the complex with protein. Electron microscopic studies also confirmed the polymolecular form of the dye in the dye-protein complex. The computational simulation of dye-dye and dye-protein interaction was performed in a model system. The micelle in the system was represented by three molecules of Congo Red. The peptide loop composed of amino acids 68-88 originating from VL IgG domain, was selected to represent protein. Amino acid side chains of this fragment were reduced to C beta. The best fitness was found for peptide chains of twisted beta conformation and independently optimized conformation of the dye in a form of "twisted ribbon" micelle. It was concluded that the IgG domains become accessible for penetration of the dye after being relaxed in the result of heating or interaction with the antigen.