Comparative Structure-Affinity Relations by MTD for Binding of Cycloadenosine Monophosphate Derivatives to Protein Kinase Receptors (original) (raw)

A “testkit” series of 27 derivatives of cAMP with various substituents in position 1, 2, 6 and 8 and within the purine cycle, thiophosphoric acid derivatives (with equatorial or axial S-atom) also included, were used to map four receptor sites of the R-subunit of cAMP dependent phosphokinases I and II, namely labile and stable receptors AI, BI, AII and BII. A QSAR by the MTD method was applied for the four series of activities, together with the relative nitrogen base hydrophobicity (lgKw), electric charge of the position 6-substituent (qN) and an indicator variable (δ = 1 for equatorial thiophosphoric derivatives). Correlation coefficients between r = 0.836 and 0.948 were obtained and the reliability of QSAR results was tested by a cross validation-like procedure. Characteristic steric features (concerning the effects of substituents in different nitrogen-base positions) were separately obtained for each receptor. For AI and BI receptor there is a negatively charged receptor group interacting with substituents in position 6 of cAMP derivatives. BI and BII receptors are of a marked hydrophobic character. Thiophosphoric acid derivatives, especially those with equatorial S-atom, have a decreased affinity for all four receptors. The results are compared with other QSAR studies of our group, concerning different series of cAMP derivatives.