Estudo teorico das relações entre estrutura quimica e atividade biologica de antagonistas do calcio da classe 1,4-diidropiridinas

AUTOR(ES)

Anderson Coser Gaudio

DATA DE PUBLICAÇÃO

1992

RESUMO

We have made a theoretical study whose purpose is to correlate the geometrical and physico-chemical properties of a series of 45 compounds to their biological activities. The compounds used in this study were the 2,6-dimethyl-3,5-carbomethoxy-4-(substituted)-phenyl-1,4-dihydropyridine (DHP) derivatives, where a large variety of functional groups were substituted in many positions of the phenyl ring. We used quantitative values of the DHP biological activity published elsewhere. Fistly we analysed conformation of the series of molecules and determined the AM1 rotational barrier of the phenyl ring in relation to the pyridine ring. Using some statistical mechanics calculation, we constructed conformational percentage maps that indicate the level of energy which would encompass 99% of the molecules at 37°C. We superposed each of these maps, separated in groups of five compounds according to their biological activities, and it was possible to select common conformational stability regions for the torsional angle linking the two rings. After that, we optimized the geometry of each molecule and calculated many physicochemical properties like ionization potential, electronic aftinity, total and partial dipolar moments, net atomic charges of the phenyl carbons, molecular polarizability, van der Waals volume, some frontier indices and some others. We correlated this properties to the biological activity through linear regression analysis. Many interesting correlations have emerged from the regression analysis and they were used to clarify some aspects that influence the DHP biological mechanism of action. Moreover, the obtained correlations, associated to the conformational analysis. helped us to propose a simplified model for the receptor site of this drugs.

ASSUNTO(S)

fisico-quimica calcio - antagonistas

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