Construction of a fused grid-based template system of CYP2C9 and its

A ligand-accessible space in the CYP2C9 active site was reconstituted as a fused grid-based Template with the use of structural data of the ligands. CYP2C9 Template generated has been developed as an evaluation system of CYP2C9 metabolism 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 CYP2C9 and its ligands through the simultaneous plural-contact with Rear-wall of Template. CYP2C9 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 as Width-gauge. The results indicate that ligand sittings are stabilized through contacts with Facial-wall and the leftside border of Template including specific Position 29 or Left-end after Trigger-residue movement. In addition, Trigger-residue movement is suggested to force ligands to stay firmly in the active site and then initiate CYP2C9 reactions. Simulation experiments for over 500 reactions of CYP2C9 ligands supported the system established. Possible modes of enhanced catalyzes in bi-molecule bindings are also discussed. ?? 2022 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Automated summary

A ligand-accessible space in the CYP2C9 active site was reconstituted as a fused grid-based template, and the interaction between CYP2C9 and its ligands was studied. The results suggest that contacts with the template walls stabilize the ligand binding, and trigger-residue movement initiates CYP2C9 reactions.