Abstract:
Cytochrome P450 is a family of enzymes situated in the human liver which is estimated to be responsible for over 75% phase I drug metabolism. To improve current in silico methods we have developed a preliminary algorithm for predicting the cytochrome P450 mediated major metabolic site of drug-like compounds. This study was aimed to determine whether bond dissociation energy (BDE) and lipophilicity play key roles in determining where the major metabolic site occurs for drug-like compounds. All C-H BDEs were calculated with quantum chemical software using density function theory (DFT). A hundred different C-H experimental values were gathered for the purpose of benchmarking them with theoretically calculated BDEs which gave an extremely strong linear correlation (R2 = 0.9746) between the experimental BDEs and the theoretically calculated values. Following on from this, all the C-H BDEs were calculated for 50 drug-like compounds with known major hydrogen abstraction sites. It was found that the average C-H BDE of the major hydrogen abstraction sites are lower on average than that of all other C-H sites (p-value = 7.257x10-9). From examining the results it was determined that C-H BDEs along with lipophilicity, steric accessibility and the presence of tertiary amines, secondary amines and alkoxy's all play key roles in determining where the major hydrogen abstraction site occurs for any give compound.
