The Use of Substituent Constants in the Correlation of Demethylation Rates

Hansch, Corwin; Ar, Steward; Iwasa, Junkichi

doi:10.1021/jm00330a035

Cited by 58 publications

(42 citation statements)

References 2 publications

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“…ships QSAR , pioneered by Hansch and coworkers in the 1960s. Here it is assumed that the sum of the steric, electronic, and hydrophobic effects of substituents in a compound determines its biological activity; see, for example, Fujita, 48 Hansch, 49 and more recently Selassie et al…”

Section: Derivation Of the Empirical Binding Free Energy Functionmentioning

confidence: 99%

Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function

et al. 1998

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A novel and robust automated docking method that predicts the bound conformations of flexible ligands to macromolecular targets has been developed and tested, in combination with a new scoring function that estimates the free energy change upon binding. Interestingly, this method applies a Lamarckian model of genetics, in which environmental adaptations of an individual's phenotype are reverse transcribed into its genotype and become Ž . heritable traits sic . We consider three search methods, Monte Carlo simulated annealing, a traditional genetic algorithm, and the Lamarckian genetic algorithm, and compare their performance in dockings of seven protein᎐ligand test systems having known three-dimensional structure. We show that both the traditional and Lamarckian genetic algorithms can handle ligands with more degrees of freedom than the simulated annealing method used in earlier versions of AUTODOCK, and that the Lamarckian genetic algorithm is the most efficient, reliable, and successful of the three. The empirical free energy function was calibrated using a set of 30 structurally known protein᎐ligand complexes with experimentally determined binding constants. Linear regression analysis of the observed binding constants in terms of a wide variety of structure-derived molecular properties was performed. The final model had a residual standard y1 Ž y1 . error of 9.11 kJ mol 2.177 kcal mol and was chosen as the new energy

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Section: Derivation Of the Empirical Binding Free Energy Functionmentioning

confidence: 99%

Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function

et al. 1998

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“…1) f ~,AF.O,,,~, -6% log k m 0%. 2) Now substituent constants from model systems can be utilized in an extrathermodynamic approach (4) to evaluate substituent effects on k,, as shown in Eq. 3.…”

Section: Methodsmentioning

confidence: 99%

“…For in vivo use, one would first have t o determine a0 (2) and then work close to this value, making maximum use of u, in designing derivatives. The problem of penetration of the blood-brain barrier which appears t o be a limiting factor in the clinical use of the tetrahydrofolate analogs, aminopterin and amethopterin ( 2 2 ) , could be circumvented by proper lipophilic design of the drug (23).…”

Section: I11mentioning

confidence: 99%

Structure-Activity Analysis of Tetrahydrofolate Analogs Using Substituent Constants and Regression Analysis

Miller

Hansch

1967

Journal of Pharmaceutical Sciences

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“…In fact, several observations indicate that both the lipophilic and ionic part of a given molecule influence its binding to membranes [10J and its metabolic fate. For example, the relative rate of in vivo and in vitro oxidation of a large series of alkyl amines was found to increase with their lipid solubility [40,45,80,83]. Conversely, the rate of biotransformation was shown to be inversely related to the pKa values of these amines, i.e.…”

Section: Figures 5 Andmentioning

confidence: 99%

“…Conversely, the rate of biotransformation was shown to be inversely related to the pKa values of these amines, i.e. the more basic the amines, the less readily were they demethylated [45,80]. The interplay between the lipid solubility and the basic functions of given amphiphilic compounds seems to govern their interaction with cellular membranes of various types.…”

Section: Figures 5 Andmentioning

confidence: 99%

Ultrastructural and biochemical study of the action of benzoctamine and maprotiline on the rat liver

et al. 1974

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The changes induced in the liver epithelium of male rats by two dibenzobicyclo octadiene analogues, maprotiline and benzoetamine, were compared. Maprotiline at high dose levels produced induction of microsomal membranes and of constituent enzymes of the endoplasmie reticulum (ER), preceded by the appearance of altered peribiliary structures, part of which showed the morphological aspect of myeloid bodies. These particles, which appeared to develop at the expense of peribiliary dense bodies, were considered to be of a lysosomal nature by virtue of their acid phosphatase activity. All the hepatic changes induced by maprotiline proved to be reversible upon cessation of treatment. Since changes similar to those caused by maprotiline were also induced by amitriptyline, imipramine and chlorpromazine, they may conceivably be produced nonspecifically by lipophilic bases. Benzoctamine, being of a less basic nature, was found to induce reversible hypertrophy of the SER only.

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The Use of Substituent Constants in the Correlation of Demethylation Rates

Cited by 58 publications

References 2 publications

Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function

Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function

Structure-Activity Analysis of Tetrahydrofolate Analogs Using Substituent Constants and Regression Analysis

Ultrastructural and biochemical study of the action of benzoctamine and maprotiline on the rat liver

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