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Homology modeling and molecular docking study of metabotropic glutamate receptor 5 variant F: an attempt to develop drugs for treating CNS diseases.

Authors :
Ahmad, Nasir
Khan, Khalid
Rashid, Haroon ur
Khan, Sher Wali
Umar, Muhammad Naveed
Gulfam, Naila
Zahoor, Muhammad
Ullah, Riaz
Ali, Essam A.
Source :
Zeitschrift für Physikalische Chemie; Aug2024, Vol. 238 Issue 8, p1551-1577, 27p
Publication Year :
2024

Abstract

G protein-coupled receptors (GPCRs) constitute the largest protein family involved in signal transduction and are the main targets for drug delivery. The metabotropic glutamate receptors (mGluRs) are class C of GPCRs that contribute to the modulation of glutamatergic neurotransmission which regulates vital physiological processes and is recognized as a potential therapeutic target throughout the central nervous system. Intracellular C-terminal domains of mGluR are the main targets for proteins regulating these receptors and are also involved in alternative splicing, regulation by phosphorylation, and modulatory protein-protein interactions. Class C of GPCRs exist as dimers and is mediated by interactions between the venus tryflap domain and the transmembrane domain. The mGluR5 variant F can be regulated by both positive and negative allosteric modulators that can potentiate or inhibit the endogenous ligand and glutamate, respectively. Moreover, mGluR5 is involved in many disorders including fragile X syndrome/autism spectrum disorder, schizophrenia, anxiety, addiction, chronic pain and epilepsy, etc. The main purpose of current computational work is to determine the 3D structures of the target protein and their active sites to design new drug molecules as potential biochemical agents. The 3D model of the mGluR5 variant F was constructed through homology modeling techniques using MOE and I-TESSER programs. RAMPAGE and ERRATE online servers were used for the 3D structure evaluation and validation. Furthermore, the mGluR5 variant F was docked with 20 mavoglurant derivatives that act as antagonists. Mavoglurant derivatives 3, 4, 6, 10, 13, 18, and 19 showed a maximum of four interactions with the mGluR5 variant F, whereas derivatives 7, 8, 9, 11, 12, 15, 16, 17 and 20 showed a maximum of three interactions with the mGluR5 variant F. The remaining four mavoglurant derivatives expressed two interactions each with mGluR5 variant F. The docking score for these derivatives ranged between −15.55 and −08.210 kcal mol<superscript>−1</superscript> suggesting their strong interactions with the mGluR5 variant F. Their 3D structure and docking study provides a potential base for the synthesis of new drug candidates to treat brain disorders. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
09429352
Volume :
238
Issue :
8
Database :
Complementary Index
Journal :
Zeitschrift für Physikalische Chemie
Publication Type :
Academic Journal
Accession number :
179508841
Full Text :
https://doi.org/10.1515/zpch-2023-0449