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

Śliwa, Paweł (Faculty of Chemical Engineering and Technology, Cracow University of Technology, 24 Warszawska Street, Kraków, 31‐155, Poland ) ; Kurczab, Rafał (Institute of Pharmacology, Polish Academy of Sciences, Department of Medicinal Chemistry, 12 Smȩtna Street, Kraków, 31‐343, Poland ) ; Bojarski, Andrzej J. (Institute of Pharmacology, Polish Academy of Sciences, Department of Medicinal Chemistry, 12 Smȩtna Street, Kraków, 31‐343, Poland ) ;
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    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 50 > 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 Q660 3.28 and/or Y805 6.55 were the anchoring points for all the studied analogs of FITM, while the H‐bond with T815 7.38 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 L757 5.44 , F801 6.51 , or W798 6.48 . 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.


  • 주제어

    fragment molecular orbital .   G protein‐coupled receptor .   mGluR1 .   ONIOM.  

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