Some methods of obtaining quantitative structure-activity relationships for quantities of environmental interest.

Receptor site binding is shown to be localized in selected atoms or substructures with relatively minor contributions from the remaining molecular framework. Related compounds can be overlayed to form a lowest common structure or hyper‐molecule that defines every possible binding site for the series. Any attempt to analyze binding data on an atom‐by‐atom basis would clearly fail if all or most of the positions were involved in the energetics. In most data sets, analysis becomes feasible when most of the variance depends on a minority of the total occupied positions. This appears to be the case in most of the sets analyzed to date, providing us with a unique opportunity. By using atomic descriptors to model lipophilicity, London forces, steric repulsion and charge interactions, the binding site can be mapped by regression analysis. Each important site of interaction and the nature of the binding force can be clearly identified. This procedure provides a statistical method based on measured data that fully complements the visual fitting of modeled drugs into defined receptor sites by computer graphics. It has enormous potential for analysis of drug, agrochemical and toxicological binding data where crystallized enzymes and fully defined sites are unknown and may long remain so. The method is illustrated by examples drawn from acetylcholinesterase receptor site binding.

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An analysis of complex alkyl‐substituent effects in the water‐catalyzed hydrolysis of 1‐acyl‐1,2,4‐triazoles

Mooij

Engberts

Charton

1988

Recl. Trav. Chim. Pays‐Bas

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Abstract. Pseudo-first-order rate constants and thermodynamic activation parameters have been determined for the water-catalyzed hydrolysis of the l-acyl-l,2,4-triazoles 1-9 in water and in aqueous acetonitrile [x(H,O) = 0.801. The reaction occurs via water-catalyzed nucleophilic attack of water at the amide carbonyl group. Variation of the alkyl group in the acyl part of the substrate led to the sequence of reactivities (in water):This complex behavior strongly suggests the operation of a composite steric effect most likely involving contributions from conformational preference (SEI), change of coordination number at carbonyl carbon (SE2), steric repulsion between 0' and the alkyl group (SE3), and steric inhibition of solvation (SE4). Modelling of the relative rates in water in terms of the expanded branching equation gave satisfactory results. Two possible transition states are proposed for the neutral hydrolysis, one involving intramolecular hydrogen bonding between the second water molecule and N2 of the 1,2,4-triazole ring. The different sequence of reactivities for neutral hydrolysis in aqueous acetonitrile as well as the rates for hydroxide-ion-catalyzed hydrolysis in water (B,,2 mechanism) support the analysis of substituent effects.

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Some methods of obtaining quantitative structure-activity relationships for quantities of environmental interest.

Cited by 5 publications

References 16 publications

The Quantitative Description of Amino Acid, Peptide, and Protein Properties and Bioactivities

The Quantitative Description of Amino Acid, Peptide, and Protein Properties and Bioactivities

A new Approach to Active‐Site Binding Analysis. Inhibitors of Acetylcholinesterase

An analysis of complex alkyl‐substituent effects in the water‐catalyzed hydrolysis of 1‐acyl‐1,2,4‐triazoles

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