Three Dimensional-Quantitative Structure Activity Relationship (3D-QSAR) Analysis Of Human CYP51 Inhibitors

CYP51 fulfills an essential requirement for all cells, by catalyzing three sequential monooxidations within the cholesterol biosynthesis cascade. Inhibition of fungal CYP51 is used as a therapy for treating fungal infections, while inhibition of human CYP51 has been considered as a pharmacological approach to treat dyslipidemia and some forms of cancer. In order to predict the interaction of inhibitors with the active site of human CYP51, a 3-dimensional quantitative structure activity relationship (3D-QSAR) model was constructed. This pharmacophore model of the common structural features of CYP51 inhibitors was built using the program Catalyst TM from multiple inhibitors (n = 26) of recombinant human CYP51-mediated lanosterol 14α-demethylation. The pharmacophore, which consisted of 1 hydrophobe, 1 hydrogen bond acceptor and 2 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 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. In order to better understand how inhibitors fit into the enzyme, potent CYP51 inhibitors were used to build a Cerius 2 TM 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 database mining. This article has not been copyedited and formatted. The final version may differ from this version. DMD #13888 4 Cytochrome P450 enzymes (CYPs) are a widely studied, large superfamily of heme-thiolate proteins involved in the metabolism of endobiotics and xenobiotics across eukaryotes and prokaryotes (Nelson et al., 1996). The clinical relevance of CYPs is their central role in drug metabolism, which can occur in all human tissues and may be inhibited by the co-administration of competing xenobiotics for the same enzyme (Wrighton et al., 1995). Much less is known about the endogenous functions of P450, although their role in steroid metabolism is an exception. It has been postulated that other endogenous roles might be in neurotransmitter metabolism (Hiroi et al., 1998) and signaling pathways (Chan et al., 1998). One of these enzymes is the ubiquitously expressed CYP51, also known as lanosterol 14 α−demethylase (P450-14DM) (Nelson et al., …