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

Abstract

The 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.

Recognition of repulsive and attractive regions of selected serotonin receptor binding site using FMO-EDA approach

“…Here, we studied complexes which would require much higher calculation costs. Recently, a similar calculation protocol (ONIOM and next FMO) was applied by us to study metabotropic glutamate receptor 1 [7].…”

“…The FMO calculations were performed for the ligand and receptor binding site. This strategy has been applied recently to other GPCRs [7,11,18]. The FMO input commands were set as default.…”

“…The FMO methodology was successfully applied to various large biological systems, primarily in a retrospective analysis of binding sites [5][6][7][8][9][10][11][12][13][14][15][16], but also as a tool supporting drug design [17][18][19][20]. Among these, several studies [7,11,16,18] have focused on one of the most important groups of biological targets, a G protein-coupled receptors (GPCRs) family. The authors found crucial interactions that were often ignored by structure-based descriptions and indicated that the FMO scheme would be a valuable tool for structure-based drug design by estimations of the chemical character of the proteins binding site.…”

“…The optimized complexes were then subjected to ab initio FMO-EDA calculations at the MP2/6-31G* level of theory. We recently applied a similar scheme to investigate the allosteric binding site of the other GPCR-metabotropic glutamate receptor 1 [7]. To the best of our knowledge, this is the first study that employed ONIOM and FMO to analyze the structure of the orthosteric binding site of selected GPCRs.…”

Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors

“…Recently in 2018, quantum mechanical methods were used to study the binding site of FITM in the mGlu 1 7TM domain and compare it with twelve close analogs covering a broad range of affinity [48]. The binding site geometries were optimized using the “our own N-layered integrated molecular orbital and molecular mechanics” (ONIOM) method along with the fragment molecular orbital method with energy decomposition analysis (FMO-EDA).…”