Abstract

The drug development process utilizes the parallel assessment of activity at a therapeutic target as well as absorption, distribution, metabolism, excretion, and toxicity properties of molecules. The development of novel, reliable, and inexpensive computational methods for the early assessment of metabolism and toxicity is becoming increasingly an important part of this process. We have used a computational approach for the assessment of drugs and drug-like compounds which bind to the cytochromes P450 (P450s) with experimentally determined K_m values. The physicochemical properties of these compounds were calculated using molecular descriptor software and then analyzed using Kohonen self-organizing maps. This approach was applied to generate a P450-specific classification of nearly 500 drug compounds. We observed statistically significant differences in the molecular properties of low K_m molecules for various P450s and suggest a relationship between 33 of these compounds and their CYP3A4-inhibitory activity. A test set of additional CYP3A4 inhibitors was used, and 13 of 15 of these molecules were colocated in the regions of low K_m values. This computational approach represents a novel method for use in the generation of metabolism models, enabling the scoring of libraries of compounds for their K_m values to numerous P450s.