Construction of a fused grid-based CYP2C19-Template system and the application.

A ligand-accessible space in the CYP2C19 active site was reconstituted as a fused grid-based Template with the use of structural data of the ligands. An evaluation system of CYP2C19-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 CYP2C19 and its ligands through the simultaneous plural-contact with Rear-wall of Template. CYP2C19 was expected to have a room for ligands between vertically standing parallel walls termed Facial-wall and Rear-wall, which were separated by a distance corresponding to 1.5-Ring (grid) diameter size. The ligand sittings were stabilized through contacts with Facial-wall and the left-side borders of Template including specific Position 29 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 CYP2C19 reactions. Simulation experiments for over 450 reactions of CYP2C19 ligands supported the system established.

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Declaration of competing interest The authors declare no conflict of interest.