AmineDB: Large scale docking of amines with CYP2D6 and scoring for druglike properties—towards defining the scope of the chemical defense against foreign amines in humans

Abstract

Organic amines are prevalent in nature and in drugs, especially the psychotherapeutic agents, and a major defense against potentially toxic amines is metabolism by CYP2D6. In order to understand better the constraints on the broad specificity of CYP2D6, 4207 amines were docked into the binding site of this enzyme. Docking poses were found predominantly with the positively charged amino groups closest to Asp301, with aromatic rings close to Phe120 and sometimes extending as far as Phe483. Organic amines that bind best to CYP2D6 tend to have larger molecular weights and logP values. Organic amines that score highly as being druglike, based on a Bayesian model constructed using a 5223-drug training set, are least likely to bind to CYP2D6. This correlation suggests that the set of known drugs, which have been largely designed or selected to avoid high affinity CYP binding, partially encodes the binding site preferences (or rather anti-preferences) of CYP2D6. Finally, in order to benchmark our docking and druglike scoring procedures, an analysis of psychotherapeutic agents is presented. All of these data, including the 4207 AM1-optimized ligand structures in proper ionization states, docking poses and scores, Druglike Scores and Lipinski properties, can be viewed from an online database, the AmineDB.

Key Words::

• CYP2D6
• substrate docking
• amines and CYP2D6
• modeling of CYP2D6
• AmineDB