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.

Keywords: GPCR; allosteric modulator; homology model; ligand-based design; mGlu; mGluR; molecular dynamics; structure-based design; virtual screening.

Figure 1

Pie chart showing reported ligands for mGlu receptors in the Thomson Reuters Integrity database. The most explored are mGlu₅, mGlu₂, and mGlu₁. Extracted on 29 January 2019 and compared with results from March 2017.

Figure 2

The structure of mGlu receptors: (a) Structure of the full length apo mGlu₅ receptor homodimer showing the VFT, CRD, and 7TM domains (PDB 6N52); (b) X-ray structures of mGlu₁ and mGlu₅ receptor 7TMs showing the different depth of binding for NAMs. (c) Close up view of the X-ray structures of the 7TM domains showing the overlay of NAMs FITM (orange) and mavoglurant (magenta) bound at mGlu₁ and mGlu₅ receptors with several amino acids labelled.

Figure 3

Chemical structures of selected ligands for mGlu₁ and mGlu₅ receptors.

Figure 4

(a) The mGlu₅ 7TM showing amino acids identified from experimental mutagenesis as important for allosteric modulator activity, compared with (b) the overlap of the subsequent X-ray crystal structures of multiple mGlu₅ receptor NAMs.

Figure 5

Origin of the functional effect of mGlu₂ PAMs and mGlu₂ NAMs. A combined experimental and computational study by Perez-Benito et al. [82] showed that PAMs and NAMs bind above the transmission switch but transmit a different conformational effect. Based on the modelling, amino acids in the transmission switch were proposed for experimental mutagenesis that confirmed their importance for receptor activation. Thus, validating a hypothesis of local allosteric modulator induced conformational changes that promote or block movements of amino acids responsible for functional activity, overall confirming the 7TM analogy with class A GPCRs.

Figure 6

Ligand-based approaches leading to identification of new mGlu₂ PAMs. (a) The structural alignment and pharmacophore of selected mGlu₂ receptor PAMs. (b) The electrostatic fields showing the similarity between pyridone and subsequent imidazopyridine and triazopyridine scaffolds.