Use of computational and experimental data to model organic compound reactivity in cytochrome P450 mediated reactions and to optimize the design of pharmaceuticals

A computer implemented method for predicting the regiospecific metabolism of a compound metabolized by one or more enzymes with broad substrate specificity, the method comprising:

• (a) providing two or more equations, each relating one or more quantum chemical descriptors to the activation energy of a metabolic transformation of a functional group on the compound, where at least two of the two or more equations (i) do not account for steric interactions of the compound with the one or more enzymes, (ii) were generated by parameterizing one or more expressions for quantum chemical activation energy with experimental data, and (iii) separately predict activation energy for at least a first enzyme-mediated reaction and a second enzyme-mediated reaction;
• (b) applying the two or more equations to two or more separate functional groups on the compound to thereby predict an activation energy value associated with the metabolic transformation of each of the two or more separate functional groups, wherein the metabolic transformation of at least one functional group comprises the first enzyme-mediated reaction and the metabolic transformation of at least one other functional group comprises the second enzyme-mediated reaction;
• and
• (c) predicting the regiospecific metabolism of the compound based on the activation energy values identified at (b).