COMPUTER CALCULATION-BASED QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS FOR THE OXIDATION OF PHENOL DERIVATIVES HORSERADISH-PEROXIDASE COMPOUND-II

The second-order rate constants for the oxidation of a series of pheno l derivatives by horseradish peroxidase compound II were compared to c omputer-calculated chemical parameters characteristic for this reactio n step. The phenol derivatives studied were phenol, 4-chlorophenol, 3- hydroxyphenol, 3-methylphenol, 4-methylphenol, 4-hydroxybenzoate, 4-me thoxyphenol and 4-hydroxybenzaldehyde. Assuming a reaction of the phen olic substrates in their non-dissociated, uncharged forms, clear corre lations (r = 0.977 and r = 0.905) were obtained between the natural lo garithm of the second-order rate constants (In k(app) and ln k(2) resp ectively) for their oxidation by compound II and their calculated ioni sation potential, i.e. minus the energy of their highest occupied mole cular orbital [E(HOMO)]. In addition to this first approach in which t he quantitative structure-activity relationship (QSAR) was based on a calculated frontier orbital parameter of the substrate, in a second an d third approach the relative heat of formation (Delta Delta HF) calcu lated for the process of one-electron abstraction and H-. abstraction from the phenol derivatives was used as a parameter. Plots of the natu ral logarithms of the second-order rate constants (k(app) and k(2)) fo r the reaction and the calculated Delta Delta HF values for the proces s of one-electron abstraction also provide clear QSARs with correlatio n coefficients of -0.968 and -0.926 respectively. Plots of the natural logarithms of the second-order rate constants (k(app) and k(2)) for t he reaction and the calculated Delta Delta HF values for the process o f H-. abstraction provide QSARs with correlation coefficients of -0.98 9 and -0.922 respectively. Since both mechanisms considered, i.e. init ial electron abstraction versus initial H-. abstraction, provided clea r QSARs, the results could not be used to discriminate between these t wo possible mechanisms for phenol oxidation by horseradish peroxidase compound II. The computer calculation-based QSARs thus obtained for th e oxidation of the various phenol derivatives by compound II from hors eradish peroxidase indicate the validity of the approaches investigate d, i.e. both the frontier orbital approach and the approach in which t he process is described by calculated relative heats of formation. The results also indicate that outcomes from computer calculations on rel atively unrelated phenol derivatives can be reliably compared to one a nother. Furthermore, as the actual oxidation of peroxidase substrates by compound II is known to be the rate-limiting step in the overall ca talysis by horseradish peroxidase, the QSARs of the present study may have implications for the differences in the overall rate of substrate oxidation of the phenol derivatives by horseradish peroxidase.