ONIOM and FMO-EDA study of metabotropic glutamate receptor 1: Quantum insights into the allosteric binding site
Authors:
- Paweł Śliwa,
- Rafał Kurczab,
- Andrzej J. Bojarski
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 allostericmodulator) and its twelve close structural analogs with a broad spectrum of affinities (2.4nM < 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 themolecular geometries of the receptor with complexed ligands, which were then used to performthe ab initio calculations using the fragment molecular orbitals method with energy decompositionanalysis (FMO-EDA). The results clearly showed that residues Q6603.28and/or Y8056.55were theanchoring points for all the studied analogs of FITM, while the H-bond with T8157.38determinedonly the orientation of very active molecules containing an amino substituent in the pyrimidinemoiety (e.g., FITM). The orientation of the other parts of ligands resulted from hydrophobic inter-actions mainly with L7575.44,F8016.51,orW7986.48.TheappliedONIOM/FMO–EDA approachfacilitated the study of effects related to very small changes in the ligand structure and led to con-clusions regarding the significance of individual interactions in the allosteric binding pocket ofmGluR1.
- Record ID
- CUT4ba33ee205104dfbbd0e8ed2138b48b2
- Publication categories
- ;
- Author
- Journal series
- International Journal of Quantum Chemistry, ISSN 0020-7608, e-ISSN 1097-461X
- Issue year
- 2018
- Vol
- 118
- No
- 15
- Pages
- [1-12]
- Other elements of collation
- rys.; wykr.; Bibliografia (na s.) - 10-12; Bibliografia (liczba pozycji) - 96; Oznaczenie streszczenia - Abstr.; Data udostępnienia on-line - 2018-03-01; Numeracja w czasopiśmie - Vol. 118, Iss. 15
- Keywords in English
- fragment molecular orbital, G protein-coupled receptor, mGluR1, ONIOM
- DOI
- DOI:10.1002/qua.25617 Opening in a new tab
- URL
- http://onlinelibrary.wiley.com/doi/10.1002/qua.25617/full Opening in a new tab
- Language
- eng (en) English
- Score (nominal)
- 20
- Additional fields
- Indeksowana w: Web of Science, Scopus
- Uniform Resource Identifier
- https://cris.pk.edu.pl/info/article/CUT4ba33ee205104dfbbd0e8ed2138b48b2/
- URN
urn:pkr-prod:CUT4ba33ee205104dfbbd0e8ed2138b48b2
* presented citation count is obtained through Internet information analysis, and it is close to the number calculated by the Publish or PerishOpening in a new tab system.