ArticlePLoS computational biology2018
The E2.65A mutation disrupts dynamic binding poses of SB269652 at the dopamine D2 and D3 receptors.
Article in PLoS computational biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Unraveling Activation-Related Rearrangements and Intrinsic Divergence from Ligand-Specific Conformational Changes of the Dopamine D3 and D2 Receptors.Journal of chemical information and modeling · 2024Review
- Synthesis of bitopic ligands based on fallypride and evaluation of their affinity and selectivity towards dopamine DEuropean journal of medicinal chemistry · 2023Article
- Unraveling activation-related rearrangements and intrinsic divergence from ligand-induced conformational changes of the dopamine D3 and D2 receptors.bioRxiv : the preprint server for biology · 2023Article
- Allosteric Modulators of Dopamine DMolecules (Basel, Switzerland) · 2022Review
- Allosteric modulation of dopamine DPharmacological reports : PR · 2022Article
- The Impact of the Secondary Binding Pocket on the Pharmacology of Class A GPCRs.Frontiers in pharmacology · 2022Review
- Chiral Cyclic Aliphatic Linkers as Building Blocks for Selective Dopamine DJournal of medicinal chemistry · 2021Article
- Structure Activity Relationships for a Series of Eticlopride-Based Dopamine DJournal of medicinal chemistry · 2021Article
- Pharmacological Characterization of the Imipridone Anticancer Drug ONC201 Reveals a Negative Allosteric Mechanism of Action at the DMolecular pharmacology · 2021Article
- Novel Dual-Target μ-Opioid Receptor and Dopamine DJournal of medicinal chemistry · 2021Article
- Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics.Pharmaceuticals (Basel, Switzerland) · 2020Review
- Novel Positive Allosteric Modulators of µ Opioid Receptor-Insight from In Silico and In Vivo Studies.International journal of molecular sciences · 2020Article
- Evidence for a Stereoselective Mechanism for Bitopic Activity by Extended-Length Antagonists of the DACS chemical neuroscience · 2020Article
- Exception That Proves the Rule: Investigation of Privileged Stereochemistry in Designing Dopamine DACS medicinal chemistry letters · 2020Article
- Ligand with Two Modes of Interaction with the Dopamine DACS chemical neuroscience · 2020Article
- The Significance of Chirality in Drug Design and Synthesis of Bitopic Ligands as DJournal of medicinal chemistry · 2019Article
- Insights From Molecular Dynamics Simulations of a Number of G-Protein Coupled Receptor Targets for the Treatment of Pain and Opioid Use Disorders.Frontiers in molecular neuroscience · 2019Review
- Exploring Substrate Binding in the Extracellular Vestibule of MhsT by Atomistic Simulations and Markov Models.Journal of chemical information and modeling · 2018Article
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8 authors.
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Abstract
The dopamine D2 and D3 receptors (D2R and D3R) are important targets for antipsychotics and for the treatment of drug abuse. SB269652, a bitopic ligand that simultaneously binds both the orthosteric binding site (OBS) and a secondary binding pocket (SBP) in both D2R and D3R, was found to be a negative allosteric modulator. Previous studies identified Glu2.65 in the SBP to be a key determinant of both the affinity of SB269652 and the magnitude of its cooperativity with orthosteric ligands, as the E2.65A mutation decreased both of these parameters. However, the proposed hydrogen bond (H-bond) between Glu2.65 and the indole moiety of SB269652 is not a strong interaction, and a structure activity relationship study of SB269652 indicates that this H-bond may not be the only element that determines its allosteric properties. To understand the structural basis of the observed phenotype of E2.65A, we carried out molecular dynamics simulations with a cumulative length of ~77 μs of D2R and D3R wild-type and their E2.65A mutants bound to SB269652. In combination with Markov state model analysis and by characterizing the equilibria of ligand binding modes in different conditions, we found that in both D2R and D3R, whereas the tetrahydroisoquinoline moiety of SB269652 is stably bound in the OBS, the indole-2-carboxamide moiety is dynamic and only intermittently forms H-bonds with Glu2.65. Our results also indicate that the E2.65A mutation significantly affects the overall shape and size of the SBP, as well as the conformation of the N terminus. Thus, our findings suggest that the key role of Glu2.65 in mediating the allosteric properties of SB269652 extends beyond a direct interaction with SB269652, and provide structural insights for rational design of SB269652 derivatives that may retain its allosteric properties.
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