TY - JOUR T1 - Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 493 LP - 500 DO - 10.1124/dmd.106.013888 VL - 35 IS - 3 AU - Sean Ekins AU - Dayna C. Mankowski AU - Dennis J. Hoover AU - Michael P. Lawton AU - Judith L. Treadway AU - H. James Harwood, Jr. Y1 - 2007/03/01 UR - http://dmd.aspetjournals.org/content/35/3/493.abstract N2 - CYP51 fulfills an essential requirement for all cells, by catalyzing three sequential mono-oxidations within the cholesterol biosynthesis cascade. Inhibition of fungal CYP51 is used as a therapy for treating fungal infections, whereas inhibition of human CYP51 has been considered as a pharmacological approach to treat dyslipidemia and some forms of cancer. To predict the interaction of inhibitors with the active site of human CYP51, a three-dimensional quantitative structure-activity relationship model was constructed. This pharmacophore model of the common structural features of CYP51 inhibitors was built using the program Catalyst from multiple inhibitors (n = 26) of recombinant human CYP51-mediated lanosterol 14α-demethylation. The pharmacophore, which consisted of one hydrophobe, one hydrogen bond acceptor, and two ring aromatic features, demonstrated a high correlation between observed and predicted IC50 values (r = 0.92). Validation of this pharmacophore was performed by predicting the IC50 of a test set of commercially available (n = 19) and CP-320626-related (n = 48) CYP51 inhibitors. Using predictions below 10 μM as a cutoff indicative of active inhibitors, 16 of 19 commercially available inhibitors (84%) and 38 of 48 CP-320626-related inhibitors (79.2%) were predicted correctly. To better understand how inhibitors fit into the enzyme, potent CYP51 inhibitors were used to build a Cerius2 receptor surface model representing the volume of the active site. This study has demonstrated the potential for ligand-based computational pharmacophore modeling of human CYP51 and enables a high-throughput screening system for drug discovery and data base mining. The American Society for Pharmacology and Experimental Therapeutics ER -