Quantitative molecular similarity analysis (QMSA) methods for property estimation: A comparison of property-based,arbitrary, and tailored similarity spaces

Three classes of arbitrary quantitative molecular similarity analysis (QMSA) methods have been computed using atom pairs, topological indices, and physicochemical properties. Tailored QMSA models have been developed using a selected number of TIs chosen by ridge regression. The methods have been applied to the K -nearest neighbor based estimation of log P of two sets of chemicals. Results show that the property-based and tailored QMSA methods are superior to the arbitrary similarity methods in estimating log P of both sets of chemicals     

Optimal neighbor selection in molecular similarity: comparison of arbitrary versus tailored prediction spaces

Three classes of arbitrary quantitative molecular similarity analysis (QMSA) methods have been computed using atom pairs (APs), topological indices (TIs), and principal components (PCs) derived from topological indices. Tailored QMSA models have been developed from TIs selected through ridge regression. K-nearest neighbor (kNN) based estimation has been applied to all of the methods to estimate normal vapor pressure (p(vap)) and water solubility (sol) for a set of 194 chemicals. Results show that the tailored QMSA methods are superior to arbitrary similarity methods in estimating both of these properties for the given set of chemicals.     

A review and examination of the mathematical spaces underlying molecular similarity analysis

As an intuitive concept, molecular similarity has played a fundamental role in chemistry. It is implicit in Hammiond's postulate, in the principle of minimum structure change, and in the assumption that similar structures tend to have similar properties, With the advent of large computers, computable definitions of similarity are being used in the pharmaceutical industry for similarity searching, dissimilarity selection, molecular superpositioning, structure generation, and quantitative structure-activity analysis. The diversity of applications of computable definitions of molecular similarity has often obscured important mathematical commonalities underlying these definitions. The broadest commonalities are relationships based of equivalence, matching, partial ordering, and proximity. A mathematical space suitable for molecular similarity analysis consists of a set of mathematical structures and one or more of these similarity relationships defined on that set. This report Surveys the mathematical spaces used in molecular similarity analysis. The survey covers the types of chemical information, similarity relationships, and applications associated with the use of each mathematical space in a molecular similarity context.     

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.     

Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods

Summary Methylphenidate (MP) binds to the cocaine binding site on the dopamine transporter and inhibits reuptake of dopamine, but does not appear to have the same abuse potential as cocaine. This study, part of a comprehensive effort to identify a drug treatment for cocaine abuse, investigates the effect of choice of calculation technique and of solvent model on the conformational potential energy surface (PES) of MP and a rigid methylphenidate (RMP) analogue which exhibits the same dopamine transporter binding affinity as MP. Conformational analysis was carried out by the AM1 and AM1/SM5.4 semiempirical molecular orbital methods, a molecular mechanics method (Tripos force field with the dielectric set equal to that of vacuum or water) and the HF/6-31G* molecular orbital method in vacuum phase. Although all three methods differ somewhat in the local details of the PES, the general trends are the same for neutral and protonated MP. In vacuum phase, protonation has a distinctive effect in decreasing the regions of space available to the local conformational minima. Solvent has little effect on the PES of the neutral molecule and tends to stabilize the protonated species. The random search (RS) conformational analysis technique using the Tripos force field was found to be capable of locating the minima found by the molecular orbital methods using systematic grid search. This suggests that the RS/Tripos force field/vacuum phase protocol is a reasonable choice for locating the local minima of MP. However, the Tripos force field gave significantly larger phenyl ring rotational barriers than the molecular orbital methods for MP and RMP. For both the neutral and protonated cases, all three methods found the phenyl ring rotational barriers for the RMP conformers/invertamers (denoted as cte, tte, and cta) to be: cte, tte> MP > cta. Solvation has negligible effect on the phenyl ring rotational barrier of RMP. The B3LYP/6-31G* density functional method was used to calculate the phenyl ring rotational barrier for neutral MP and gave results very similar to those of the HF/6-31G* method.     

Systematic statistical comparison of comparative molecular similarity indices analysis molecular fields for computer-aided lead optimization

Comparative molecular similarity indices analysis (CoMSIA) is a 3D quantitative structure-activity relationship technique used to determine structural and electronic features influencing biological activity. This proves particularly useful for facilitating lead optimization projects. This study aimed to compare CoMSIA models produced using different subsets of the CoMSIA molecular fields (steric, electrostatic, hydrophobic, hydrogen-bond donor, and hydrogen-bond acceptor) in a systematic and statistically valid manner. A total of 23 data sets sourced from the literature were used to compare molecular field contribution and model predictivity using leave-one-out cross-validated R2 values. Predictive ability varied in a highly statistically significant manner depending on the set of CoMSIA molecular fields used. In general, the greater the number of CoMSIA molecular fields included in the analysis, the better the model predictivity was. There is great redundancy in the information contained in the different CoMSIA molecular fields. When all five CoMSIA molecular fields are included, the hydrophobic and electrostatic fields had the largest and the steric field the smallest contribution. Data sets were clustered into four groups on the basis of the utility of molecular field sets to generate predictive models.     

A comparison of field-based similarity searching methods: CatShape, FBSS, and ROCS

Three field-based similarity methods are compared in retrospective virtual screening experiments. The methods are the CatShape module of CATALYST, ROCS, and an in-house program developed at the University of Sheffield called FBSS. The programs are used in both rigid and flexible searches carried out in the MDL Drug Data Report. UNITY 2D fingerprints are also used to provide a comparison with a more traditional approach to similarity searching, and similarity based on simple whole-molecule properties is used to provide a baseline for the more sophisticated searches. Overall, UNITY 2D fingerprints and ROCS with the chemical force field option gave comparable performance and were superior to the shape-only 3D methods. When the flexible methods were compared with the rigid methods, it was generally found that the flexible methods gave slightly better results than their respective rigid methods; however, the increased performance did not justify the additional computational cost required.     

Crystal structure,magnetic property and DFT analysis for a bis(tetracyanoquinodimethane)zinc(II) complex

A bis(tetracyanoquinodimethane)zinc(II) complex (1) was structurally characterized, in which the Zn²⁺ ion occupies at an inversion centre and is bonded to two tetracyanoquinodimethane radical anions (TCNQ^?), two H₂O and two DMF molecules to form almost perfectly octahedral coordination geometry. The strong H-bonding interactions are observed between H₂O molecules as well as between H₂O molecule and TCNQ^? radical anion of the neighboring complex molecules, additionally, there exist π?π stack interactions between TCNQ^? radical anions. The intermolecular H-bonding and π?π stack interactions lead to a supramolecular network sheet forming on the crystallographic ac-plane, and the neighboring supramolecular network sheets further extend into three-dimensional supramolecular structure via weak van der Waals forces. Symmetry-broken approach in the theoretical formwork of DFT for magnetic exchange constants analysis disclosed that the ground state of 1 is singlet state, the excited triplet state is much closed to the nonmagnetic ground state with a small energy gap of 1.25 × 10^?5 eV, and there exist AFM interaction in the TCNQ π-stacks, and these predictions are in agreement with magnetic susceptibility measurements.     

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a series of thiazolone derivatives as novel inhibitors bound to the allosteric site of hepatitis C virus (HCV) NS5B polymerase were developed based on CoMFA and CoMSIA analyses. Two different conformations of the template molecule and the combinations of different CoMSIA field/fields were considered to build predictive CoMFA and CoMSIA models. The CoMFA and CoMSIA models with best predictive ability were obtained by the use of the template conformation from X-ray crystal structures. The best CoMFA and CoMSIA models gave q (2) values of 0.621 and 0.685, and r (2) values of 0.950 and 0.940, respectively for the 51 compounds in the training set. The predictive ability of the two models was also validated by using a test set of 16 compounds which gave r (pred) (2) values of 0.685 and 0.822, respectively. The information obtained from the CoMFA and CoMSIA 3D contour maps enables the interpretation of their structure-activity relationship and was also used to the design of several new inhibitors with improved activity.     

SAXS from a poly(amido-amine)-heparin complex in aqueous solutions: a comparison between two analysis methods

Summary Joerchel's method is applied to SAXS spectra of a poly(amido-amine)-heparin complex in aqueous non diluted solutions, showing a noticeable interference effect. The results are compared with those obtained by the classical Guinier analysis applied to diluted solutions of the complex.

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Zusammenfassung SAXS-Spektren eines Poly(amido-amin)-Heparin-Komplexes in nicht verdünnten wäßrigen Lösungen, die bemerkenswerte Interferenzeffekte zeigen, wurden mittels der Joerchel'schen Methode analysiert. Die Ergebnisse wurden mit den durch die klassische Analyse von Guinier an verdünnten wäßrigen Komplexlösungen erhaltenen verglichen.

     

A comparison of two methods for selecting vibrational configuration interaction spaces on a heptatomic system: ethylene oxide

Two recently developed methods for solving the molecular vibrational Schrodinger equation, namely, the parallel vibrational multiple window configuration interaction and the vibrational mean field configuration interaction, are presented and compared on the same potential energy surface of ethylene oxide, c-C(2)H(4)O. It is demonstrated on this heptatomic system with strong resonances that both approaches converge towards the same fundamental frequencies. This confirms their ability to tackle the vibrational problem of large molecules for which full configuration interaction calculations are not tractable.     

The application of fourier-transformed near-infrared spectra to quantitative analysis by comparison of similarity indices (CARNAC)

A new technique for utilising near-infrared spectroscopic data for quantitative analysis is proposed. The method uses a database of spectra stored in the form of the Fourier transform together with the associated chemical analysis. The spectrum of an unknown sample is compared to each member of the database and a small subset of very similar samples is isolated. The analyte value for the unknown is calculated from the analytical values of the subset. Results are given for the application of the method to the analysis of nicotine in tobacco.     

Estimation of molecular similarity based on 4D-QSAR analysis: formalism and validation

The 4D-QSAR paradigm has been used to develop a formalism to estimate molecular similarity measures as a function of conformation, alignment, and atom type. It is possible to estimate the molecular similarity of pairs of molecules based upon the entire ensemble of conformational states each molecule can adopt at a given temperature, normally room temperature. Molecular similarity can be measured in terms of the types of atoms composing each molecule leading to multiple measures of molecular similarity. Multiple measures of molecular similarity can also arise from using different alignment rules to perform relative molecular similarity, RMS, analysis. An alignment independent method of determining molecular similarity measures, referred to as absolute molecular similarity, AMS, analysis has been developed. Various sets and libraries of compounds, including the amino acids, are analyzed using 4D-QSAR molecular similarity analysis to demonstrate the features of the formalism. Exploration of molecular similarity as a function of chirality, identification of common embedded 3D pharmacophores in compounds, and elucidation of 3D-isosteric compounds from structurally diverse libraries are carried out in the application studies.     

Quantitative chromatographic analysis using rectified radio-frequency methods: Lithium,sodium and potassium

The blake Zone Detector has been shown to be a very useful apparatus for the location of ion zones separated by paper Chromatography. In the case of the alkali metals, these zones can be estimated by measuring the impedance of their aqueous extract. An alternative method, that of measuring the area under the detector curve, does not provide a practical means of quantitative measurement, A new developing solvent is described for the paper Chromatographic separation of lithium, sodium and potassium chlorides.