title: Three-dimensional quantitative structure-activity relationship analysis of human CYP51 inhibitors.
abstract: 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 14alpha-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 IC(50) values (r = 0.92). Validation of this pharmacophore was performed by predicting the IC(50) of a test set of commercially available (n = 19) and CP-320626-related (n = 48) CYP51 inhibitors. Using predictions below 10 microM 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 Cerius(2) 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.
authors.affiliation: Computational Biology, ACT LLC, 601 Runnymede Ave., Jenkintown, PA 19046, USA. ekinssean@yahoo.com
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.forename: Dayna C
authors.initials: DC
authors.lastname: Mankowski
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Hoover
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lawton
authors.forename: Judith L
authors.initials: JL
authors.lastname: Treadway
authors.forename: H James
authors.initials: HJ
authors.lastname: Harwood
mesh_terms: D000577:Amides / Q000737:chemistry; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000737:chemistry; D008958:Models, Molecular; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D021281:Quantitative Structure-Activity Relationship; D058886:Sterol 14-Demethylase
chemical_list: D000577:Amides; C548418:CYP51A1 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; C412544:CP 320626