Parameters and Methods in Quantitative Structure-Activity Relationships

Osman, Roman; Weinstein, Harel; Green, Jack Peter

doi:10.1021/bk-1979-0112.ch002

Cited by 16 publications

(10 citation statements)

References 56 publications

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“…The Taft steric substituent constant is of interest in its own right and has been useful in biological QSAR [Osman et al, 1979;Hansch, 19781. In fact, the problems associated with the three-dimensional character of molecules is one of the more underdeveloped areas of QSAR work.…”

Section: Steric Parametersmentioning

confidence: 99%

Structure‐activity relationships (SARs) among mutagens and carcinogens: A review

1986

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This review is an introduction to methods for evaluating structure-activity relationships (SARs), and, in particular, to those methods that have been applied to study mutagenicity and carcinogenicity. A brief history and some background material on the earliest attempts to correlate molecular structure and biological activity are included. Most of the discussion focuses on modern methods utilizing extrathermodynamic and physical property variables such as the Hansch method and SIMCA, and approaches based on molecular connectivity such as the ADAPT, CASE, and Enslein methods. In general, the latter class is potentially the most useful in the study of the large and structurally diverse databases so often encountered in the study of mutagenicity and carcinogenicity. They also are not very sensitive to lab-to-lab variances in reported activities and outright misclassifications in activities of some compounds. This is chiefly because the statistical treatments used in these methods tend to dilute the importance of outliers. The methods using physicochemical and extrathermodynamic variables are especially important in relatively small, congeneric databases and can help fine-tune the role of physicochemical properties in mechanistic hypotheses. All of the above methods have been used to look at mutagenicity and carcinogenicity and some of the results reported in the literature are reviewed here. As far as specific methods go, ADAPT, CASE, SIMCA and the Enslein approach all seem to have similar classification powers (in the range of 75-95%), depending very much on the database studied. The emphasis in this review is on showing that the use of these computer-aided storage, retrieval and analysis techniques is a timely approach to predicting and even understanding the toxicity of environmental substances. However, each of the methods discussed is still under development, and their potential usefulness for predictive purposes is still being explored.

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Section: Steric Parametersmentioning

confidence: 99%

Structure‐activity relationships (SARs) among mutagens and carcinogens: A review

1986

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“…However, these reactivity criteria are often artificially constructed parameters with no obvious formal relationship to recognition and activity, whereas the electrostatic potential generated by a molecule is an experimentally observable quantity from high energy electron scattering (46) For example, in a series of studies on the molecular determinants for recognition and activity at the receptors of the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) a major recognition element is the electrostatic potential (24,48). We showed that the MEP over the indole portion of 5-HT congeners, and of congeners of lysergic acid diethylamide (LSD), has a characteristic directionality that can be represented by an electrostatic orientation vector.…”

Section: C12mentioning

confidence: 99%

“…If, however, the toxicity of the molecule is related to its ability to act as a whole, e.g., by intercalation,then a more relevant representation of the MEP would be on a surface around the molecule. These two simple examples illustrate the manner in which MEP maps can be used, and have been used in the past [e.g., see (57) for localized values, and (24,47,48) for values on surfaces] to obtain information about the reactivity characteristics of drugs in relation to specific mechanistic propositions. As a screening procedure, however, this approach is strongly dependent on information about the mechanism and is therefore less general than required for a selection of MEP characteristics relevant to broadly defined toxicity.…”

Section: New Approaches To the Calculation Of Mep And The Analysis Ofmentioning

confidence: 99%

“…In other studies we examined the relation between quantitative SAR (QSAR), molecular structure, and biological activity (24,48,77,78), and showed that reactivity characteristics obtained from MEP and from the higher-order terms (El l and E2,0) provide a link between the various forms of SAR studies. For example, in the case of drugs acting at the biological receptor of the neurotransmitter 5-hydroxytryptamine, maps ofthe polarizability (ES ,,) indicated the molecular regions that are most readily polarizable and are therefore most likely to contribute to the stabilization of electron donor-acceptor complexes (77,83).…”

Section: The Gradient Of Mep (The Electric Fieldmentioning

confidence: 99%

“…This consideration reveals one of the major drawbacks of the approaches in which structure-activity relationships (SAR) are studied on the basis of parameters representing contributions from certain structural components (functional groups, substituents). These parameters used in "quantitative SAR" (QSAR) often fail to provide a reliable relationship between molecular structure and biological activity for they seldom constitute an adequate representation of molecular properties (24). Useful predictive criteria for biological activity should therefore be constructed from molecular properties derived from the entire molecular structure because their role in determining various aspects of molecular activity can be understood on the basis of clear physicochemical principles.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Determinants of Molecular Reactivity as Criteria for Predicting Toxicity: Problems and Approaches

Weinstein¹,

Rabinowitz²,

Liebman³

et al. 1985

Environmental Health Perspectives

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We discuss the physicochemical basis for mechanisms of action of toxic chemicals and theoretical methods that can be used to understand the relation to the structure of these chemicals. Molecular properties that determine the chemical reactivity of the compounds are proposed as parameters in the analysis of such structure-activity relationships and as criteria for predicting potential toxicity. The theoretical approaches include quantitative methods for structural superposition of molecules and for superposition of their reactivity characteristics. Applications to polychlorinated hydrocarbons are used to illustrate both rigid superposition methods, and methods that take advantage of structural flexibility. These approaches and their results are discussed and compared with methods that afford quantitative structural comparisons without direct superposition, with special emphasis on the need for efficient automated methods suitable for rapid scans of large structural data bases. Quantum mechanical methods for the calculation of molecular properties that can serve as reactivity criteria are presented and illustrated. Special attention is given to the electrostatic properties of the molecules such as the molecular electrostatic potential, the electric fields, and the polarizability terms calculated from perturbation expansions. The practical considerations related to the rapid calculation of these properties on relevant molecular surfaces (e.g., solvent-or reagent-accessible surfaces) are discussed and exemplified, stressing the special problems posed by the structural variety of toxic substances and the paucity of information on their mechanisms of action. The discussion leads to a rationale for the use of the combination of theoretical methods to reveal discriminant criteria for toxicity and to analyze the initial steps in the metabolic processes that could yield toxic products.

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Computergestütztes Moleküldesign (CAMD) – ein Überblick

1987

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Ein neues Instrument, in der Ingenieurtechnik bereits seit langem als CAD etabliert, zieht in die Laboratorien der chemischen Forschung ein : Computer-Assisted Molecular Design (CAMD). Der kombinierte Einsatz von Computergraphik und Theoretischer Chemie eroffnet neue Perspektiven fur die molekiilorientierte Forschung. Strukturen und ihre Eigenschaften wie Raumfiillung, Ladungsverteilung oder dynamisches Verhalten k6nnen bestimmt und miteinander verglichen werden. Beim Umgang mit komplexen Systemen wie groI3en Biomolekulen (protein engineering) ist diese neue Arbeitsweise bereits unentbehrlich.Angew. Chem. 99 (1987) 413-428 0 VCH Verlagsgesellschafi mbH, 0-6940 Weinheim, 1987 0044-8249/87/0505-04413 S 02.50/0 5.5). Ahb. I. a) Skelettmodell des tnzyms Renin (gclh) n i t Blick in den Hohlraum des aktiven Zentrums (blau). im unteren Bildteil ein Modellinhibitor (blau). b)Hohlraum des aktiven Zentrums (gelb) mit schlecht eingepaDtem Inhibitor (blau). Rote Vektoren zeigen ,,hot spots" an. Der Komplex hat eine Energie von 14220.53 kcal/mol. c) Optimal eingepaoter Inhibitor. Die Energie ist deutlich geringer als in b) (180.61 kcal/mol).

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Parameters and Methods in Quantitative Structure-Activity Relationships

Cited by 16 publications

References 56 publications

Structure‐activity relationships (SARs) among mutagens and carcinogens: A review

Structure‐activity relationships (SARs) among mutagens and carcinogens: A review

Determinants of Molecular Reactivity as Criteria for Predicting Toxicity: Problems and Approaches

Computergestütztes Moleküldesign (CAMD) – ein Überblick

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