Construction of a fused grid-based CYP2C8-Template system and the application

A ligand-accessible space in the CYP2C8 active site was reconstituted as a fused grid-based Template∗ with the use of structural data of the ligands. An evaluation system of CYP2C8-mediated metabolism has been developed on Template with the introduction of the idea of Trigger-residue initiated ligand-movement and fastening. Reciprocal comparison of the data of simulation on Template with experimental results suggested a unified way of the interaction of CYP2C8 and its ligands through the simultaneous plural-contact with Rear-wall of Template. CYP2C8 was expected to have a room for ligands between vertically standing parallel walls termed Facial-wall and Rear-wall. Both the walls were separated by a distance corresponding to 1.5-Ring (grid) diameter size, which was termed Width-gauge. The ligand sittings were stabilized through contacts with Facial-wall and the left-side borders of Template including specific Position 29, left-side border of Rings I/J, or Left-end, after Trigger-residue initiated ligand-movement. Trigger-residue movement is suggested to force ligands to stay firmly in the active site and then to initiate CYP2C8 reactions. Simulation experiments for over 350 reactions of CYP2C8 ligands supported the system established.