title: Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: discovery and computational modeling of a new series of ligands with nanomolar affinity.
abstract: Metabotropic glutamate receptor 5 (mGlu5) is a biological target implicated in major neurological and psychiatric disorders. In the present study, we have investigated structural determinants of the interaction of negative allosteric modulators (NAMs) with the seven-transmembrane (7TM) domain of mGlu5. A homology model of the 7TM receptor domain built on the crystal structure of the mGlu1 template was obtained, and the binding modes of known NAMs, namely MPEP and fenobam, were investigated by docking and molecular dynamics simulations. The results were validated by comparison with mutagenesis data available in the literature for these two ligands, and subsequently corroborated by the recently described mGlu5 crystal structure. Moreover, a new series of NAMs was synthesized and tested, providing compounds with nanomolar affinity. Several structural modifications were sequentially introduced with the aim of identifying structural features important for receptor binding. The synthesized NAMs were docked in the validated homology model and binding modes were used to interpret and discuss structure-activity relationships within this new series of compounds. Finally, the models of the interaction of NAMs with mGlu5 were extended to include important non-aryl alkyne mGlu5 NAMs taken from the literature. Overall, the results provide useful insights into the molecular interaction of negative allosteric modulators with mGlu5 and may facilitate the design of new modulators for this class of receptors.
authors.affiliation: Life Sciences Department, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy.
authors.forename: Andrew
authors.initials: A
authors.lastname: Anighoro
authors.affiliation: Drug Discovery Department, Recordati S.p.A. Via Civitali 1, 20148 Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Graziani
authors.affiliation: Drug Discovery Department, Recordati S.p.A. Via Civitali 1, 20148 Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bettinelli
authors.affiliation: Drug Discovery Department, Recordati S.p.A. Via Civitali 1, 20148 Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cilia
authors.affiliation: Drug Discovery Department, Recordati S.p.A. Via Civitali 1, 20148 Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: De Toma
authors.affiliation: Drug Discovery Department, Recordati S.p.A. Via Civitali 1, 20148 Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Longhi
authors.affiliation: Drug Discovery Department, Recordati S.p.A. Via Civitali 1, 20148 Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Mangiarotti
authors.affiliation: Drug Discovery Department, Recordati S.p.A. Via Civitali 1, 20148 Milan, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Menegon
authors.affiliation: Drug Discovery Department, Recordati S.p.A. Via Civitali 1, 20148 Milan, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Pirona
authors.affiliation: Drug Discovery Department, Recordati S.p.A. Via Civitali 1, 20148 Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Poggesi
authors.affiliation: Drug Discovery Department, Recordati S.p.A. Via Civitali 1, 20148 Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Riva
authors.affiliation: Life Sciences Department, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy. Electronic address: giulio.rastelli@unimore.it.
authors.forename: Giulio
authors.initials: G
authors.lastname: Rastelli
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D055808:Drug Discovery; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry*; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D007093:Imidazoles; D008024:Ligands; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C032794:fenobam; C121465:6-methyl-2-(phenylethynyl)pyridine
keywords: Docking; Homology modeling; Metabotropic glutamate receptor 5; Negative allosteric modulators