QSAR Applications Research Articles

On the Topological Sub-Structural Molecular Design (TOSS-MODE) in QSPR/QSAR and Drug Design Research

A recently introduced graph-theoretical approach to the study of structure-property-activity relationships is presented. The theoretical approach and the computational strategy for the use of the TOSS-MODE approach are given with details. Several QSPR and QSAR applications are reviewed including the study of physical properties of organic compounds, diamagnetic susceptibilities, and biological properties. The applications of the TOSS-MODE approach to discrimination of active/inactive compounds, the virtual screening of compounds with a desired property from databases of chemical structures, identification of active/inactive fragments and its relationships with 2D/3D pharmacophores, and to the design of novel compounds with desired biological activities are also reviewed.

Classical QSAR and comparative molecular field analyses of the host-guest interaction of organic molecules with cyclodextrins.

The application of classical QSAR and molecular modeling analysis using Comparative Molecular Field Analysis (CoMFA) to the complexation of some natural and modified cyclodextrins (CDs) with guest molecules was examined. For 1:1 complexation systems between natural beta-CD, modified alpha-, beta-, and gamma-CD that bear one p-(dimethylamino)benzoyl (DMAB) moiety (DMAB-alpha-, beta-, and gamma-CDs) and guest molecules of widely varying chemical structures and properties, the binding constants of the complexes were successfully fitted using multiple linear regression (MLR) with hydrophobic descriptor log P (the partition coefficient between 1-octanol and water phases) and molecular connectivity indices. A non-linear dependency of binding constants on the zero-th and/or first order molecular connectivity index as a measure of size becomes apparent. The modeling performance of the CoMFA models with steric/electrostatic fields to DMAB-alpha- and beta-CD systems was comparable to those of MLR models. However, statistically significant CoMFA models for gamma-CD systems which have higher conformational flexibility of the ring could not be obtained. The CoMFA models obtained for DMAB-alpha- and beta-CD systems showed that the predominant effects were steric for the DMAB-alpha-CD system and electrostatic for the DMAB-beta-CD system, respectively.

QSAR study on antibacterial and antifungal activities of some 3,4-disubstituted-1,2,4-oxa(thia)-diazole-5(4 H)-ones(thiones) using physicochemical, quantumchemical and structural parameters

This work demonstrated the quantitative structure-activity relationships of 3,4-disubstituted-1,2,4-oxa(thia)-diazole-5(4 H)-ones (thiones) using quantum chemical parameter R( I), hydrophobicity descriptor and structural parameters. Semiempirical molecular orbital calculations were used to determine the quantum chemical parameter R( I), which is the electron density of HOMO at the sulfur and oxygen in position 1 of the compounds investigated, divided by the orbital energy of HOMO. It was shown that the electron density of HOMO at the sulfur and oxygen of the molecules was strongly related to the biological activities of these molecules. The results obtained from the QSAR application indicated that there was a parabolic dependence between the biological activities and the R( I) index. The structural factor I Y which shows the presence of a sulfur atom in position 1 was the dominant predictor for the antibacterial and antifungal activities. On the other hand, the other structural variable I X which shows the presence of a sulfur atom double bonded to the C atom in position 5 caused a decrease, but the hydrophobicity of the whole molecule (Σ) caused an increase in activity.

Chemical Property Calculation through JavaScript and Applications in QSAR

The inorganic property (I) and organic property (O) values of general organic groups are re-proposed here. Both I and O values of drug and biological molecules or groups can be calculated based on their common group values. The calculation can be performed easily on-line through JavaScript. Similar calculation can be done for the drug and biological molecular group electronegativity (X) according to the author's published paper. The calculation of lipophilicity (π or logP) parameter of (macro)molecules (like proteins) can also be performed on-line through JavaScript. Two equations expressed with I and O are provided here to define the hydrophobicity of each amino acid. The correlations of inorganic property and organic property values with other parameters are also discussed. These calculated parameters combined with other parameters can be used for QSAR studies in some drug molecules.

Analysis of the Ecetoc Aquatic Toxicity (EAT) database I — General introduction

In assessing the environmental risk of a chemical it is necessary to predict safe levels in the environment, but this requires extrapolation from relatively small databases. To improve understanding of the use of existing data for such extrapolations, the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) established a Task Force to assemble a high-quality database on aquatic toxicity from published papers. The database contains over 2200 records of effects of about 360 substances on 121 aquatic species. Computer programs were developed to enter, search for, retrieve and analyse the data. Output consisted of simple counts, frequency distributions and regression analyses by which (for example) comparisons of different life-stages, species-sensitivity and acute:chronic ratios, and application of QSARs could be examined for use in risk assessment. This paper describes the content of the database, the methods of analysis and gives a brief comparison of acute: chronic ratios: four subsequent papers describe the results.

QUANTIFICATION OF NON-COVALENT INTERACTIONS ON THE BASIS OF THE THERMODYNAMIC HYDROGEN BOND PARAMETERS

This paper describes how empirical free energy and/or enthalpy values for hydrogen binding strength are derived from thousands of corresponding measurements between H-bond donors and acceptors, mostly in carbon tetrachloride, and how they can be used to construct common scales or factor values (increments) also for other reactions involving electron donor and acceptor ability of functions. The corresponding databases and programs (HYBOT) allow one to predict thermodynamic values for experimentally unknown equilibria, including also ionophore complexes with crown ethers or cryptands. Applications in QSAR involve the prediction of lipophilicity from any structure on the basis of only two variables, e.g. 234 systems are described this way with a correlation coefficient r=0·96. Similarly, permeabilities and some biological properties such as narcotic activities of chemicals and anti-HIV-1 activity of some porphyrins are evaluated. © 1997 John Wiley & Sons, Ltd.

QUANTIFICATION OF NON‐COVALENT INTERACTIONS ON THE BASIS OF THE THERMODYNAMIC HYDROGEN BOND PARAMETERS

This paper describes how empirical free energy and/or enthalpy values for hydrogen binding strength are derived from thousands of corresponding measurements between H-bond donors and acceptors, mostly in carbon tetrachloride, and how they can be used to construct common scales or factor values (increments) also for other reactions involving electron donor and acceptor ability of functions. The corresponding databases and programs (HYBOT) allow one to predict thermodynamic values for experimentally unknown equilibria, including also ionophore complexes with crown ethers or cryptands. Applications in QSAR involve the prediction of lipophilicity from any structure on the basis of only two variables, e.g. 234 systems are described this way with a correlation coefficient r=0·96. Similarly, permeabilities and some biological properties such as narcotic activities of chemicals and anti-HIV-1 activity of some porphyrins are evaluated. © 1997 John Wiley & Sons, Ltd.

Evaluation of Critical Body Residue QSARS for Predicting Organic Chemical Toxicity to Aquatic Organisms

The critical body residue (CBR) is the concentration of chemical bioaccumulated in an aquatic organism that corresponds to a defined measure of toxicity (e.g., mortality). The CBR can provide an alternative measure of toxicity to traditional waterborne concentration measurements (e.g., concentration in water causing 50% mortality). The CBR has been suggested as a better estimator of dose than the external water concentration and has been postulated to be constant for chemicals with the same mode of action. CBR QSARs have both theoretical and experimental support, developed primarily from studies on the acute toxicity of narcotic chemicals to small fish. CBR QSARs are less well developed for the aquatic toxicity of non-narcotic chemicals. CBRs vary substantially with the mode of action and toxicity endpoint, and may be affected by genetic, hormonal or environmental variation. CBR QSARs may not be applicable to very hydrophobic chemicals, chemicals with specific modes of action, or those with toxicity controlled by kinetic processes such as biotransformation. CBRs models have not been developed or evaluated for sediment and dietary exposure routes. Application of CBR QSARs to contaminated site assessments will require further research and development.

Evaluation of the hydrophobic parameters of the amino acid side chains of peptides and their application in QSAR and conformational studies

Evaluation of the hydrophobic parameters of the amino acid side chains of peptides and their application in QSAR and conformational studies

Spectral Moments of the Edge-Adjacency Matrix of Molecular Graphs. 2. Molecules Containing Heteroatoms and QSAR Applications

A novel substructural approach to structure−property and structure−activity relationships studies is proposed. The method is based on the computation of spectral moments of the edge-weighted adjacency matrix. In the present work, bond distances are used as bond weights in the diagonal entries of edge matrix. Spectral moments of the edge-weighted adjacency matrix are expressed in terms of structural fragments present in molecules via algebraic expressions. Boiling points of 58 alkyl halides were well described by the present approach, and this property was expressed as a linear combination of structural fragments of the studied molecules. QSAR applications of the novel approach are explored by studying the antifungal activity of benzyl alcohols. An equation expressing contributions of each substituent in benzyl alcohols to the antifungal activity is obtained. The methodology proposed here permits the rational design of novel compounds with improved activity, which is illustrated for benzyl alcohol derivatives.

Time-efficient flexible superposition of medium-sized molecules.

We present an efficient algorithm for the structural alignment of medium-sized organic molecules. The algorithm has been developed for applications in 3D QSAR and in receptor modeling. The method assumes one of the molecules, the reference ligand, to be presented in the conformation that it adopts inside the receptor pocket. The second molecule, the test ligand, is considered to be flexible, and is assumed to be given in an arbitrary low-energy conformation. Ligand flexibility is modeled by decomposing the test ligand into molecular fragments, such that ring systems are completely contained in a single fragment. Conformations of fragments and torsional angles of single bonds are taken from a small finite set, which depends on the fragment and bond, respectively. The algorithm superimposes a distinguished base fragment of the test ligand onto a suitable region of the reference ligand and then attaches the remaining fragments of the test ligand in a step-by-step fashion. During this process, a scoring function is optimized that encompasses bonding terms and terms accounting for steric overlap as well as for similarity of chemical properties of both ligands. The algorithm has been implemented in the FLEXS system. To validate the quality of the produced results, we have selected a number of examples for which the mutual superposition of two ligands is experimentally given by the comparison of the binding geometries known from the crystal structures of their corresponding protein-ligand complexes. On more than two-thirds of the test examples the algorithm produces rms deviations of the predicted versus the observed conformation of the test ligand below 1.5 A. The run time of the algorithm on a single problem instance is a few minutes on a common-day workstation. The overall goal of this research is to drastically reduce run times, while limiting the inaccuracies of the model and the computation to a tolerable level.

Single and domain mode variable selection in 3D QSAR applications

This paper describes variable selection of grid based 3D QSAR investigations. Three steroid data sets were studied using GOLPE like variable selection as well as variable selection with contiguous domains (boxes). The predictivity of the selected variable models of the training sets was in all cases improved compared with the corresponding original models using all variables. However, the predictivity of the test sets was in a few cases only marginally improved by variable selection. Domain-based variable selection did not improve the predictivity of the external test sets.

Exploring QSAR Fundamentals and Applications in Chemistry and Biology, Volume 1. Hydrophobic, Electronic and Steric Constants, Volume 2 J. Am. Chem. Soc. 1995, 117, 9782

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTExploring QSAR Fundamentals and Applications in Chemistry and Biology, Volume 1. Hydrophobic, Electronic and Steric Constants, Volume 2 J. Am. Chem. Soc. 1995, 117, 9782David HoekmanCite this: J. Am. Chem. Soc. 1996, 118, 43, 10678Publication Date (Web):October 30, 1996Publication History Published online30 October 1996Published inissue 1 January 1996https://doi.org/10.1021/ja965433+Copyright © 1996 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views2799Altmetric-Citations9LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (20 KB) Get e-Alerts Get e-Alerts

Application of Hydrophobicity Parameters to Prediction of the Acute Aquatic Toxicity of Commercial Surfactant Mixtures

Abstract Ethoxylated alcohols are the most extensively used nonionic surfactants in detergent products. The application of QSAR to their aquatic toxicity is complicated by the fact that they are multicomponent mixtures, the parent alcohols being often mixtures of isomers and homologues, each one being ethoxylated to varying degrees. A spreadsheet method for calculation of aquatic toxicity of such nonionic surfactant mixtures is presented. The method is based on a combination of the Konemann narcosis QSAR and mixture toxicity equations based on the principle of concentration addition. Log P values used in the spreadsheet calculations are themselves calculated by spreadsheet formulae based on the Leo and Hansch method modified by incorporation of the position dependent branching factor originally applied to linear alkylbenzene sulphonates. Close agreement between calculated and experimental EC50 values (48 hr Daphnia tests) is obtained for a range of ethoxylated alcohols having a diversity of branching patt...

Reactive substructures in the prediction of aquatic toxicity data

Baseline QSAR models relating acute toxicity to log P ow are analyzed for predicting fish LC 50 data of various compounds. Mostly ( > 75%), the high dependency of aquatic toxicity on lipophilicity resulted in agreement of calculated and experimental data. Deviations occur with respect to compounds revealing excess toxicity. From fathead minnow LC 50 data for 500 organic chemicals, the toxicity of 122 compounds was found to be severely underestimated on the basis of log P ow alone. Among these ‘outliers’, 14 reactive substructures were identified, which accounted for > 73% of the compounds with excess toxicity. The application of a baseline QSAR supplemented by indicators for the reactive substructures also allowed the prediction of toxicity data based on other endpoints, indicating similar modes of interaction in various aquatic tests.

Application of QSARs in Risk Management of Existing Chemicals

QSAR-estimates of aquatic toxicity of relatively unreactive (narcosis-type) organic chemicals for 19 species were used to predict "no-effect-levels" (NELs) at the ecosystem level by means of several extrapolation models which were recently discussed by the Organisation for Economic Cooperation and Development (OECD). It appeared that the differences between the numerical results of these extrapolation methods, despite their different statistical assumptions, were small. Equilibrium-partitioning theory for sediment and water as well as biota and water was used to derive NELs for aquatic sediments and whole-body residues. Simple equations are given, from which NELs for water, and subsequently for sediments and whole-body residues, can be predicted on the basis of only the octanol-water partition coefficient. Actual application of the models presented absolutely requires the availability of methods to recognize chemicals that act by the unspecific mechanism of narcosis. To this end, a classification scheme, based on molecular structure, was developed. This classification scheme was applied to the approximately 2000 so-called High Production Volume Chemicals (HPVCs) listed in Annex 1 of the Council Regulation on the Evaluation and the Control of the Environmental Risks of Existing Chemicals of the European Communities. From the classification of these 2000 HPVCs it is concluded that, for a large portion of all existing chemicals, reliable QSAR estimates of aquatic toxicity can be made; this considerably speeds up the process of priority setting and risk assessment of existing chemicals. The validity of this (dual) approach was tested by a comparison of estimated NELs with actual FCC values for all compounds from the US-EPA Water Quality Guidelines list that classify as narcosis-type compounds. This comparison shows that for many existing chemicals QSARs may be used to derive quality guidelines for water, aquatic sediments and residues in aquatic biota.

Deactivated hydrocarbonaceous silica and immobilized artificial membrane stationary phases in high-performance liquid chromatographic determination of hydrophobicities of organic bases: relationship to log P and CLOGP.

Retention parameters for a series of 29 organic base drugs (including 17 phenothiazine derivatives) were measured by reversed-phase high-performance liquid chromatography (HPLC) employing new columns of distinctive partition properties. One column was a deactivated alkyl-bonded silica and two others were packed with lecithin-bonded propylamino-silica, i.e. the immobilized artificial membrane (IAM) columns; one of the IAM stationary phases had the unreacted propylamine moieties additionally end-capped with methylglycolate. The highly deactivated hydrocarbonaceous silica column showed regular rectilinear relationships between logarithms of chromatographic capacity factors and the content of organic modifier in aqueous eluent; it is suitable for generating a chromatographic scale of hydrophobicity. Such a scale (hydrocarbonaceous) is different from that provided by measurement of partitioning of solutes between n-octanol and water (alkanol log P scale). The relative hydrophobicity parameters determined by HPLC on the IAM columns were different from both log P scale and from the hydrocarbonaceous chromatographic hydrophobicity scale. The hydrophobicity parameter, CLOGP, theoretically calculated by the fragmental methods, correlated better than log P with chromatographic hydrophobicity parameters. It has been postulated that each hydrophobicity measuring system reveals some specific aspects of the hydrophobicity phenomenon and that the nature of hydrophobic binding sites on receptors and plasma proteins may require different hydrophobicity models than drug permeation through biological membranes. By means of HPLC, diverse hydrophobicity measures can readily be determined, among which those most suitable for specific QSAR applications can be identified.

Self‐returning walks and fractional electronic charges of atoms in molecules

AbstractThree hierarchically ordered topological factors, i.e., atom connectivity, centrality, and cyclicity, were found to control the number of self‐returning walks (SRWS) associated with every atom in the molecule. The reversal of their order was observed in a few cases where the central location of atoms had a stronger influence than did their connectivity on the number of SRWS. Three atomic topological indices, i.e., the Morgan extended connectivity, the Balaban, Mekenyan, and Bonchev hierarchical extended connectivity, the Randić atomic path code, were found to closely match the ordering of atoms in molecules determined by their number of SRWS. New atomic graph invariants fi = lim SRW/SRWn and ti = fi · SRW2 were specified and may find application in QSAR and QSPR. The ti indices are nonintegers close to atomic valence. The fi indices represent the limit of the number of SRWS of length n for the atom i, SRW, normalized by dividing it by the total number of SRWS for the molecule. In the case of Hückel MO considerations, these invariants were shown to be numerically equal to the partial electronic charges of the lowest occupied molecular orbital (LOMO). A new class of isocodal atoms (atoms having the same number of SRWns) was observed, i.e., atoms that become isocodal only at n ⩾ 1. A number of open questions following from these findings were formulated, including the possibility for a topological modeling of electron correlation. © 1993 John Wiley & Sons, Inc.

Statistical approach to chemicals classification

Principal component analysis was employed to test its applicability for classifying potential environmental contaminants by modes of action with respect to various targets. Discrimination of baseline from specific toxicants is necessary to allow the rational QSAR prediction from either log P ow, or other descriptors, thus selecting the appropriate endpoints and models. Taking pesticides from different classes with known effects as an example, a reduction of the relevant toxicity parameters was achieved by combining data sets. Based on the principal components QSARs reflecting the underlying common processes were derived. The predominance of lipophilicity-dependent baseline toxicity is indicated for various classes of compounds with respect to most endpoints, whereas the pattern of excess toxicity revealed to be specific for each target. Multivariate statistics proved to be a useful tool to recognize compounds of analogous mode of action, as required for consecutive QSAR application.

Application of QSARs, extrapolation and equilibrium partitioning in aquatic effects assessment. I. Narcotic industrial pollutants

AbstractQuantitative structure–activity relationship (QSAR) estimates of toxicity of narcotic chemicals for 19 species of bacteria, algae, fungi, protozoans, coelenterates, rotifers, molluscs, crustaceans, insects, fish, and amphibians were used to predict no‐effect levels (NELs) at the ecosystem level by means of recently developed extrapolation methods. Equilibrium partitioning theory was used to derive NELs for aquatic sediments and internal toxicant concentrations for aquatic organisms. A simple table is given from which NELs for narcotic chemicals for water, sediment, and residues in biota can be predicted on the basis of only the octanol/water partition coefficient and molecular weight. The method may be applied to setting quality criteria for the aquatic environment and to ecotoxicological interpretation of (bio)monitoring data. Calculations were carried out for 102 narcotic compounds.