ONIOM and FMO‐EDA study of metabotropic glutamate receptor 1: Quantum insights into the allosteric binding site

Abstract

AbstractThe crystal structure of metabotropic glutamate receptor 1 (mGluR1) complexed with 4‐fluoro‐N‐(4‐(6‐(isopropylamino)pyrimidin‐4‐yl)thiazol‐2‐yl)‐N‐methylbenzamide (FITM, a negative allosteric modulator) and its twelve close structural analogs with a broad spectrum of affinities (2.4 nM < IC50 > 10 000 nM) were investigated using quantum mechanical methods. The our own N‐layered integrated molecular orbital and molecular mechanics (ONIOM) was used to optimize the molecular geometries of the receptor with complexed ligands, which were then used to perform the ab initio calculations using the fragment molecular orbitals method with energy decomposition analysis (FMO‐EDA). The results clearly showed that residues Q6603.28 and/or Y8056.55 were the anchoring points for all the studied analogs of FITM, while the H‐bond with T8157.38 determined only the orientation of very active molecules containing an amino substituent in the pyrimidine moiety (e.g., FITM). The orientation of the other parts of ligands resulted from hydrophobic interactions mainly with L7575.44, F8016.51, or W7986.48. The applied ONIOM/FMO–EDA approach facilitated the study of effects related to very small changes in the ligand structure and led to conclusions regarding the significance of individual interactions in the allosteric binding pocket of mGluR1.