Unimolecular and bimolecular binding system for the prediction of CYP2D6-mediated metabolism

We have developed a template system for the prediction of CYP2D6-mediated metabolism of compounds. The system is composed of two types of two-dimensional templates (templates A and B), which were generated from mutually occupied areas of typical CYP2D6 substrates. The areas of templates are expressed as hexagonal blocks for application to the two-dimensional structures of chemicals. Experiments with 93 reactions with 69 typical substrates indicated the necessity for two similar but distinct shapes for template A (A1 and A2) for optimal placement. A frequently occupied area for substrates in template A1 was defined as a trigger area in which to capture a substrate for initiation of metabolism. Another frequently occupied area was found near the site of metabolism in template B. Both frequently occupied areas are linked to a pinching area. Occupancy of substrates on two template areas is suggested to be essential for the metabolism of CYPD6 substrates. In cases of CYP2D6 substrates without simultaneous occupancy of both areas, bimolecular placement, in which two molecules are placed coordinately, is proposed. Metabolism of small molecules, including naphthalene and quinoline, became explainable with the use of this idea. Validation of this template system with the use of both good and poor CYP2D6 substrates indicated clear advantages of the present system as a tool for drug modification, in addition to enabling highly accurate estimation of the site of metabolism.