Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors

Abstract

Metabotropic glutamate (mGlu) receptors are a family of eight GPCRs that are attractive drug discovery targets to modulate glutamate action and response. Here we review the application of computational methods to the study of this family of receptors. X-ray structures of the extracellular and 7-transmembrane domains have played an important role to enable structure-based modeling approaches, whilst we also discuss the successful application of ligand-based methods. We summarize the literature and highlight the areas where modeling and experiment have delivered important understanding for mGlu receptor drug discovery. Finally, we offer suggestions of future areas of opportunity for computational work.

The role of water and protein flexibility in the structure-based virtual screening of allosteric GPCR modulators: an mGlu5 receptor case study

“…These two conformations of Trp785 6.50 result in different shapes of the allosteric binding pocket and warn that protein flexibility and induced fit binding have to be taken into account in the molecular modelling of ligand binding to mGlu 5 receptor. This is also supported by several structure-based computational studies which were performed previously to map ligand–protein interactions and to understand irregular SAR using pharmacophore modelling, molecular docking and molecular dynamics simulations [15, 19–25]. Moreover, analysis of the X-ray structures coupled with computational water network analysis performed by WaterFLAP showed that many of the ligand–protein interactions are mediated by water molecules and this also has to be taken into account in interpreting structure–activity relationships across chemotypes.…”

Profiling the Structural Determinants of Aryl Benzamide Derivatives as Negative Allosteric Modulators of mGluR5 by In Silico Study

“…Christopher et al [22] Up to now, two mGluR5 receptor binding regions (the orthosteric binding region in the VFT and the allosteric binding region in the 7TM) have been reported [24]. In fact, we find that the studies on the NAM site almost all focus on the transmembrane allosteric binding region [8,[19][20][21][22], which can be explained by the fact that the allosteric binding pocket is less conserved compared to the orthosteric binding region, thus helping the identification of selective ligands [9]. In structure, the 8 antagonists belong to the acetylenic chemotype and non-acetylenic chemotype, as shown in Figure 8.…”

“…Factually, by observing our docking results, we can find that the active conformation of all molecules can be divided into two categories, namely "linear" and "arc" configuration, as shown in Figures 9 and 10. orthosteric binding region, thus helping the identification of selective ligands [9]. In structure, the 8 antagonists belong to the acetylenic chemotype and non-acetylenic chemotype, as shown in Figure 8.…”

“…Structurally, mGlu receptors consist of a large amino-terminal venus fly-trap (VFT) extracellular domain (encompassing the orthosteric site), a seven-transmembrane domain (7TMD), and a cysteine-rich domain (CRD) linking the two [9]. Although several crystal structures of the VFT domain are usable for some mGluR subtypes, including mGluR1, mGluR5, mGluR3, and mGluR7, the orthosteric site has proven difficult to develop efficient subtype-selective ortho-ligands due to its highly conserved characteristic [10].…”

Implications of a Neuronal Receptor Family, Metabotropic Glutamate Receptors, in Cancer Development and Progression

“…An intriguing topic for future studies is the evaluation of the role of mGluR homodimerization and/or heterodimerization in cancer development and progression. There are numerous antagonists and agonists for group I–III mGluRs, which have been extensively reviewed by multiple authors; therefore, they will not be reviewed here [ 20 , 31 , 32 , 33 , 34 ].…”