Received for publication November 14, 2006.
Revised December 21, 2006.
Accepted for publication December 26, 2006.

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

Abstract

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 14-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 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. 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.

Key words: computational models, computer modeling and simulation, CYP inhibition, structure-activity relationships

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