| 1. |
- Draper-Joyce, Christopher J., et al.
(author)
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Positive allosteric mechanisms of adenosine A(1) receptor-mediated analgesia
- 2021
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In: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 597:7877, s. 571-576
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Journal article (peer-reviewed)abstract
- The adenosine A(1) receptor (A,R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain(1,2). However, development of analgesic orthosteric A(1)R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects(3). Here we show that [2-amino-4-(3,5-bis(trifluoromethyl) phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A(1)R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the co-bound to adenosine, MIPS521 and a G(12) heterotrimer, revealing an extrahelicallipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts.
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| 2. |
- Kampen, Stefanie, et al.
(author)
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Structure-Guided Design of G-Protein-Coupled Receptor Polypharmacology
- 2021
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In: Angewandte Chemie International Edition. - : John Wiley & Sons. - 1433-7851 .- 1521-3773. ; 60:33, s. 18022-18030
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Journal article (peer-reviewed)abstract
- Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi-target profiles is rarely pursued because it is considered too difficult, in particular if the drug must enter the central nervous system. Here, a structure-based strategy to identify dual-target ligands of G-protein-coupled receptors is presented. We use this approach to design compounds that both antagonize the A(2A) adenosine receptor and activate the D-2 dopamine receptor, which have excellent potential as antiparkinson drugs. Atomic resolution models of the receptors guided generation of a chemical library with compounds designed to occupy orthosteric and secondary binding pockets in both targets. Structure-based virtual screens identified ten compounds, of which three had affinity for both targets. One of these scaffolds was optimized to nanomolar dual-target activity and showed the predicted pharmacodynamic effect in a rat model of Parkinsonism.
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| 3. |
- Matricon, Pierre, et al.
(author)
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Ligand design by targeting a binding site water
- 2021
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In: Chemical Science. - : Royal Society of Chemistry. - 2041-6520 .- 2041-6539. ; 12:3, s. 960-968
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Journal article (peer-reviewed)abstract
- Solvent reorganization is a major driving force of protein–ligand association, but the contribution of binding site waters to ligand affinity is poorly understood. We investigated how altered interactions with a water network can influence ligand binding to a receptor. A series of ligands of the A2A adenosine receptor, which either interacted with or displaced an ordered binding site water, were studied experimentally and by molecular dynamics simulations. An analog of the endogenous ligand that was unable to hydrogen bond to the ordered water lost affinity and this activity cliff was captured by molecular dynamics simulations. Two compounds designed to displace the ordered water from the binding site were then synthesized and evaluated experimentally, leading to the discovery of an A2A agonist with nanomolar activity. Calculation of the thermodynamic profiles resulting from introducing substituents that interacted with or displaced the ordered water showed that the gain of binding affinity was enthalpy driven. Detailed analysis of the energetics and binding site hydration networks revealed that the enthalpy change was governed by contributions that are commonly neglected in structure-based drug optimization. In particular, simulations suggested that displacement of water from a binding site to the bulk solvent can lead to large energy contributions. Our findings provide insights into the molecular driving forces of protein–ligand binding and strategies for rational drug design.
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| 4. |
- Panel, Nicolas, et al.
(author)
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Design of Drug Efficacy Guided by Free Energy Simulations of the β2-Adrenoceptor
- 2023
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In: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 62:22
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Journal article (peer-reviewed)abstract
- G-protein-coupled receptors (GPCRs) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if high-resolution receptor structures are available. We performed molecular dynamics simulations of the β2 adrenergic receptor in active and inactive conformations to assess if binding free energy calculations can predict differences in ligand efficacy for closely related compounds. Previously identified ligands were successfully classified into groups with comparable efficacy profiles based on the calculated shift in ligand affinity upon activation. A series of ligands were then predicted and synthesized, leading to the discovery of partial agonists with nanomolar potencies and novel scaffolds. Our results demonstrate that free energy simulations enable design of ligand efficacy and the same approach can be applied to other GPCR drug targets.
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