Composite multi-parameter ranking of real and virtual compounds for design of MC4R agonists: Renaissance of the Free-Wilson methodology

Drug design is a multi-parameter task present in the analysis of experimental data for synthesized compounds and in the prediction of new compounds with desired properties. This article describes the implementation of a binned scoring and composite ranking scheme for 11 experimental parameters that were identified as key drivers in the MC4R project. The composite ranking scheme was implemented in an AstraZeneca tool for analysis of project data, thereby providing an immediate re-ranking as new experimental data was added. The automated ranking also highlighted compounds overlooked by the project team. The successful implementation of a composite ranking on experimental data led to the development of an equivalent virtual score, which was based on Free-Wilson models of the parameters from the experimental ranking. The individual Free-Wilson models showed good to high predictive power with a correlation coefficient between 0.45 and 0.97 based on the external test set. The virtual ranking adds value to the selection of compounds for synthesis but error propagation must be controlled. The experimental ranking approach adds significant value, is parameter independent and can be tuned and applied to any drug discovery project.     

Calculation of entropy and heat capacity of organic compounds in the gas phase. Evaluation of a consistent method without adjustable parameters. Applications to hydrocarbons

The purpose of this study has been to determine how well a consistent ab initio thermostatistical method reproduces experimental values of heat capacity and entropy. The method has been applied to calculation of heat capacity and entropy of a representative set of hydrocarbons that includes compounds consisting of multiple conformers. All Cp and S values are for the gaseous state at 1 atm; units are cal K-1 mol-1. A detailed sensitivity (error) analysis has been performed to determine the root mean square (rms) values of errors expected of the calculated values: these are 0.27 cal for Cp and 0.36 cal for entropy. In comparing calculated values with experimental values, it is necessary to consider also the uncertainties of the experimental data. When these are included, the expected rms values of Cp(experimental) - Cp(calculated) values at 298.15 K range from 0.21 to 0.73. For S(experimental) - S(calculated), they range from 0.36 to 0.72. Calculations with frequencies derived with the 6-31G(d,p) basis set and scaled by 0.91 yielded rms values for Cp(experimental) - Cp(calculated) of individual compounds from 0.14 to 0.84 cal and rms values for S(experimental) - S(calculated) of individual compounds from 0.07 to 1.11 cal. Calculated Cp values for 7 out of 16 compounds agree with experimental values within the rms uncertainty estimated for the compound, and 11 fall within twice that estimate. For entropy, the calculated values for 13 of 18 compounds agree with the very limited available experimental data within the rms estimated uncertainty for the compound, and 16 of 18 fall within twice the uncertainty.     

Extraction separation and cleaning of sewage waters by organic solvents with recirculation

The technology of separation and cleaning of sewage waters from organic compounds by their extraction from water solution by isopropyl ether with its further separation and return for reuse is proposed and well founded. Results of the experimental investigations and kinetics of the liquid phase extraction of organic compounds from sewage waters are reported.     

Surface tension of different sized single-component droplets,according to macroscopic data obtained using the lattice gas model and the critical droplet size during phase formation

Size dependences of the surface tension of spherical single-component droplets are calculated using equations of the lattice gas model for 19 compounds. Parameters of the model are found from experimental data on the surface tension of these compounds for a macroscopic planar surface. The chosen low-molecular compounds satisfy the law of corresponding states. To improve agreement with the experimental data, Lennard-Jones potential parameters are varied within 10% deviations. The surface tensions of different sized equilibrium droplets are calculated at elevated and lowered temperatures. It is found that the surface tension of droplets grows monotonically as the droplet size increases from zero to its bulk value. The droplet size R ₀ corresponding to zero surface tension corresponds to the critical size of the emergence of a new phase. The critical droplet sizes in the new phase of the considered compounds are estimated for the first time.     

Multinuclear high-resolution NMR study of compounds from the ternary system NaF-CaF2-AlF3: from determination to modeling of NMR parameters

27Al and 23Na NMR satellite transition spectroscopy and 3Q magic-angle-spinning spectra are recorded for three compounds from the ternary NaF-CaF2-AlF3 system. The quadrupolar frequency nuQ, asymmetry parameter etaQ, and isotropic chemical shift deltaiso are extracted from the spectrum reconstructions for five aluminum and four sodium sites. The quadrupolar parameters are calculated using the LAPW-based ab initio code WIEN2k. It is necessary to perform a structure optimization of all compounds to ensure a fine agreement between experimental and calculated parameters. By a comparison of experimental and calculated values, an attribution of all of the 27Al and 23Na NMR lines to the crystallographic sites is achieved. High-speed 19F NMR MAS spectra are recorded and reconstructed for the same compounds, leading to the determination of 18 isotropic chemical shifts. The superposition model developed by Bureau et al. is used, allowing a bijective assignment of the 19F NMR lines to the crystallographic sites.     

Sorption of organic compounds from urine in mutagenicity testing: choice of sorbent

The choice of sorbents for urine mutagenicity testing was investigated. 14C-Labelled compounds were dissolved in urine and extracted from it by sorption with seven different sorbents singly or in combination. The compounds were desorbed with acetone. Sorption was examined under various experimental conditions. Except for two strong ionic compounds satisfactory extraction was achieved with a combination of three sorbents: Amberlite XAD-2, XAD-7, and Sep-Pak Silica. Filtration of the urine or contact of it with the walls of the experimental equipment could lead to substantial losses. Implications of these results for urine mutagenicity testing and possibilities for further optimization of the method are discussed.     

An extended saturated liquid density equation

The recently developed saturated liquid density correlation of Iglesias-Silva and Hall for halogenated paraffins is extended to other classes of compounds involving paraffins, cycloparaffins, olefins, diolefins, cyclic-olefins, aromatics, alcohols, ethers, liquefied inorganic gases, and others. The two adjustable parameters of the correlation are optimized and reported for 126 compounds. The average error for 5377 experimental data points was 0.27%. The correlation is extended to multicomponent mixtures. A set of mixing rules is proposed. The correlation with this set of mixing rules is used to predict the saturated liquid density of 86 multicomponent systems consisting of LNG, heavy hydrocarbons, CO₂, H₂S, alcohols and halogenated paraffins. The average of error for 1378 experimental data points was 1.03% with 0 bias with respect to experimental data. These values compare well with the values from well-known correlations. For polar compounds or multicomponent systems containing polar compounds, the computation of saturated liquid density by this correlation shows superiority with respect to the other correlations.     

Virtual screening and library enumeration of new hydroxycinnamates based antioxidant compounds: A complete framework

Designing of molecules for drugs is important topic from many decades. The search of new drugs is very hard, and it is expensive process. Computer assisted framework can provide the fastest way to design and screen drug-like compounds. In present work, a multidimensional approach is introduced for the designing and screening of antioxidant compounds. Antioxidants play a crucial role in ensuring that the body's oxidizing and reducing species are kept in the proper balance, minimizing oxidative stress. Machine learning models are used to predict antioxidant activity. Three hydroxycinnamates are selected as standard antioxidants. Similar compounds are searched from ChEMBL database using chemical structural similarity method. The libraries of new compounds are generated using evolutionary method. New compounds are also designed using automatic decomposition and construction building blocks. The antioxidant activity of all designed and searched compounds is predicted using machine learning models. The chemical space of searched and generated compounds is envisioned using t-distributed stochastic neighbor embedding (t-SNE) method. Best compounds are shortlisted, and their synthetic accessibility is predicted to further facilitate the experimental chemists. The chemical similarity between standard and selected compounds is also studied using fingerprints and heatmap.     

Dependence of the critical temperature on molecular parameters

At the critical temperature the surface tension between coexisting liquid and vapor phases must be zero, and the repulsive contributions associated with cavity formation must exactly counterbalance those from interactions of a molecule in the cavity and the bulk. An expression for the critical temperature of pure fluids in terms of the parameters of scaled particle theory (SPT) has been obtained, and the calculated critical temperatures are compared with experimental data for a range of pure fluids. These include noble and diatomic gases, short and medium length hydrocarbons, aromatic compounds, halogenated compounds, oxygen-containing compounds, and water. Considering the simplicity of this approach, a remarkably good correlation between calculated and experimental values is found for most of these fluids.     

Die Kristallstruktur des Calciumhydrogensulfat-Dihydrogensulfats – ein neuer Strukturtyp für schwefelsaure Hydrogensulfate

Extra-atomic Relaxation Energy — a New Physical Parameter Characterizing Chemical Bonding A new method is proposed for the determination of extra-atomic relaxation in chemical compounds. The extra-atomic relaxation is obtained as the difference between experimental and theoretical Auger parameters. The extra-atomic relaxation energy characterizes the chemical bondings ionicity of the atom under consideration with his surrounding atoms. The calculated extra-atomic relaxations are the additive function of the ligands of the atom studied. The increments of the additive scheme correlate with the ligand refraction. The method has been applied to solid compounds of the elements from Na to Cl, and to a number of free sulfur-, phosphorus-, silicon-and chlorinecontaining molecules. The obtained extra-atomic relaxation energies agree well with both calculated and direct experimental results. The application of the extra-atomic relaxation for determination of the effective atomic charge in hypothetical compounds is demonstrated for ArO₄.     

Prediction of retention times and efficiency in linear gradient programmed pressure analysis on capillary columns

A method for the prediction of the retention time and the resolution of chromatographic peaks in different experimental conditions by starting from few experimental data measured in isothermal and isobaric analyses was published previously. In this paper, the same mathematical model was implemented for calculating the retention times and the column efficiency in programmed pressure runs. Some models originated from the Golay equation and reported in the literature are compared, and a new modified equation for the calculation of the peak width at half height is proposed. The procedure for the prediction of the retention time and the peak width at half height at programmed pressure of the carrier gas and different column temperature and linear gradient by using retention data of different compounds obtained in few isobaric runs is described. The prediction of the retention time and the separation efficiency of compounds with different polarity gave good results for the programmed pressure runs with linear gradient. The effect of the variation of the initial parameters of the experimental analyses and of the mathematical model on the accuracy of the prediction has been evaluated.     

The Dawn of Functional Organoarsenic Chemistry

Organoarsenic chemistry was actively studied until the middle of 20th century. Although various properties of organoarsenic compounds have been computationally predicted, for example, frontier orbital levels, aromaticity, and inversion energies, serious concern to the danger of their synthetic processes has restricted experimental studies. Conventional synthetic routes require volatile and toxic arsenic precursors. Recently, nonvolatile intermediate transformation (NIT) methods have been developed to safely access functional organoarsenic compounds. Important intermediates in the NIT methods are cyclooligoarsines, which are prepared from nonvolatile inorganic precursors. In particular, the new approach has realized experimental studies on conjugated arsenic compounds: arsole derivatives. The elucidation of their intrinsic properties has triggered studies on functional organoarsenic chemistry. As a result, various kinds of arsenic-containing π-conjugated molecules and polymers have been reported for the last few years. In this minireview, progress of this recently invigorated field is overviewed.     

Giving molecules an identity. On the interplay between QSARs and partial order ranking

The interplay between 'noise-deficient' QSAR and Partial Order Ranking, including analysis of average linear ranks, constitutes an effective tool in giving substances which have not been investigated experimentally an identity by comparison with experimentally well-characterized, structurally similar compounds. It is disclosed that experimentally well-characterized compounds may serve as substitutes for highly toxic compounds in experimental studies without exhibiting the same extreme toxicity, while from an overall viewpoint they exhibit analogous environmental characteristics.     

Aurophilic interactions as a subject of current research: an up-date

Recently accumulated experimental evidence for aurophilic interactions in and between molecular gold(I) compounds and the results of pertinent theoretical calculations are reviewed for the period from 2007 to mid-2011. The influence of the intra- and intermolecular bonding contacts between the closed-shell metal centres, Au-Au, on the molecular and crystal structures, and the consequences of these effects for the chemical and physical properties of gold compounds are summarized for the various classes of mono- and polynuclear systems. The literature survey builds on the contents of previous reviews and relates new experimental and theoretical findings to earlier observations (353 references).     

Determination of HMO parameters with MS-Xα-SCF method

A technique for determining the HMO parameters with MS-Xα-SCF method has been developed. The ionization potentials of even polyenes and condensed benzene compounds have been calculated. The average deviation from the existent experimental values is 0.34 eV.     

New results on methylalkali systems: Accurate vibrational study of methylsodium

This paper presents results (structural parameters and anharmonic vibrational spectra) obtained for the methylsodium system at different levels of theory from DFT and post-HF [CCSD(T)] calculations. These theoretical results are faced with the existing experimental data. An interpretation of the experimental reference is proposed from our calculations about the monomer and the dimer compounds.     

Adherent and slippery walls for extrusion of entangled polymer melts and compounds

A brief overview is given of the distortions observed when polymer melts or compounds are extruded. It appears that extrusion through steel dies can be done either with macroscopic slip or with no-slip wall conditions. Recent experimental and theoretical progress made in understanding the various aspects of slip at the wall, and its measurement techniques, are presented. Boundary conditions for rubber compounds flowing through steel-walled dies could be seen to be much more complex than those for melts. However many aspects of the methodologies developed are of common interest both for melts and rubber. It has already been suggested that advantages can be obtained from the use of slippery walls in extrusion. Such wall properties have already been used indeed for a long time with compounds, where processing additives are introduced. New experimental data are presented concerning two typical EPDM compounds series, obtained using several laboratory techniques at the same time. Constitutive equations for the bulk and for friction at the wall can be introduced at present and adjusted to experimental data. Die extrusion can be simulated numerically, and significant improvements can be expected in quality and productivity.     

结合直观推导式演进特征投影法分析原油中非烃结构和含量

提出一种分析原油非烃结构和含量的方法。用直观推导式演进特征投影法分辨有关二维数据以获得非烃的纯色谱和纯质谱,再将所获质谱在标准质谱库中检索,并结合色谱保留指数分析等来进行单个非烃化合物结构鉴定;利用实验数据,根据分辨获得的纯色谱峰面积所建立的规一化模型,进行非烃化合物定量分析。用本法确定了一原油样品中168个含氮化合物和该油样一个馏分中60个其它非烃化合物的结构和含量。本方法具有系统分析原油非烃结构和含量的通用性;标准化合物加标回收实验表明,其准确度很好。