| 1. |
- Ballante, Flavio, et al.
(författare)
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Structure-Based Virtual Screening for Ligands of G Protein-Coupled Receptors : What Can Molecular Docking Do for You?
- 2021
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Ingår i: Pharmacological Reviews. - : AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS. - 0031-6997 .- 1521-0081. ; 73:4, s. 527-565
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Forskningsöversikt (refereegranskat)abstract
- G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome and are important therapeutic targets. During the last decade, the number of atomic -resolution structures of GPCRs has increased rapidly, providing insights into drug binding at the molecular level. These breakthroughs have created excitement regarding the potential of using structural information in ligand design and initiated a new era of rational drug discovery for GPCRs. The molecular docking method is now widely applied to model the threedimensional structures of GPCR-ligand complexes and screen for chemical probes in large compound libraries. In this review article, we first summarize the current structural coverage of the GPCR superfamily and the understanding of receptor-ligand interactions at atomic resolution. We then present the general workflow of structure-based virtual screening and strategies to discover GPCR ligands in chemical libraries. We assess the state of the art of this research field by summarizing prospective applications of virtual screening based on experimental structures. Strategies to identify compounds with specific efficacy and selectivity profiles are discussed, illustrating the opportunities and limitations of the molecular docking method. Our overview shows that structure-based virtual screening can discover novel leads and will be essential in pursuing the next generation of GPCR drugs. Significance Statement--Extraordinary advances in the structural biology of G protein-coupled receptors have revealed the molecular details of ligand recognition by this large family of therapeutic targets, providing novel avenues for rational drug design. Structure-based docking is an efficient computational approach to identify novel chemical probes from large compound libraries, which has the potential to accelerate the development of drug candidates.
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| 2. |
- Kampen, Stefanie, et al.
(författare)
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Structure-Based Discovery of Negative Allosteric Modulators of the Metabotropic Glutamate Receptor 5
- 2022
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 17:10, s. 2744-2752
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Tidskriftsartikel (refereegranskat)abstract
- Recently determined structures of class C G protein-coupled receptors (GPCRs) revealed the location of allosteric binding sites and opened new opportunities for the discovery of novel modulators. In this work, molecular docking screens for allosteric modulators targeting the metabotropic glutamate receptor 5 (mGlu(5)) were performed. The mGlu(5) receptor is activated by the main excitatory neurotransmitter of the nervous central system, L-glutamate, and mGlu(5) receptor activity can be allosterically modulated by negative or positive allosteric modulators. The mGlu(5) receptor is a promising target for the treatment of psychiatric and neurodegenerative diseases, and several allosteric modulators of this GPCR have been evaluated in clinical trials. Chemical libraries containing fragment-(1.6 million molecules) and lead-like (4.6 million molecules) compounds were docked to an allosteric binding site of mGlu(5) identified in X-ray crystal structures. Among the top-ranked compounds, 59 fragments and 59 lead-like compounds were selected for experimental evaluation. Of these, four fragment-and seven lead-like compounds were confirmed to bind to the allosteric site with affinities ranging from 0.43 to 8.6 mu M, corresponding to a hit rate of 9%. The four compounds with the highest affinities were demonstrated to be negative allosteric modulators of mGlu(5) signaling in functional assays. The results demonstrate that virtual screens of fragment and lead-like chemical libraries have complementary advantages and illustrate how access to high-resolution structures of GPCRs in complex with allosteric modulators can accelerate lead discovery.
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| 3. |
- Kampen, Stefanie
(författare)
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Structure-based Virtual Screening for Ligands of G Protein-coupled Receptors : Design of Allosteric and Dual-Target Modulators
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- G protein-coupled receptors (GPCRs) are integral membrane proteins responsible for signal transduction of extracellular stimuli into the cell. Because of their widespread distribution throughout the human body and important roles in physiological processes, GPCRs are prominent drug targets and approximately 34% of all approved drugs interact with members of this superfamily. GPCR ligands are used as drugs against various diseases, including neurodegenerative and neuropsychiatric disorders. The increased availability of GPCR structural information has enhanced understanding of GPCR function but also enables structure-based drug design (SBDD). This thesis focuses on SBDD targeting allosteric and orthosteric binding sites of GPCRs and strategies to identify multi-target ligands. Drug discovery campaigns are traditionally based on the one-target-one-drug paradigm, but effective treatment of complex neurological disorders generally requires modulation of several signaling pathways. In publication I, dual-target ligands that activate the D2 dopamine receptor (D2R) and antagonize the A2A adenosine receptor (A2AAR) were designed through a structure-based approach. Both GPCRs are relevant for Parkinson’s disease (PD) and animal studies support that interactions with these targets induce neuroprotection while eliciting a synergistic therapeutic effect. One of the designed ligands was shown to yield an antiparkinsonian effect in a rodent model. Publication II focuses on the identification of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor 5 (mGlu5) using structure-based virtual screening. Such modulators have been considered as a treatment of PD, fragile X syndrome and depression. The study discovered 11 allosteric modulators and four of these were also shown to be NAMs of mGlu5. Manuscript III describes the development of dual-target ligands acting as antagonists of the A2AAR and NAMs of mGlu5. Blocking the activity of both receptors has been shown to have a synergistic antiparkinsonian effect that could be both symptomatic and neuroprotective. In this study, virtual screening was used to discover drug-like compounds with submicromolar binding affinity to both targets. Publication IV presents a comprehensive review of SBDD targeting GPCRs of all classes with a specific focus on the method of molecular docking. Publication V describes a program for automatic validation of X-ray crystal structures. Possible applications involve assessment of protein structures used in SBDD or the generation of high-quality test sets for the evaluation of molecular docking methods. The results of this thesis illustrate that structure-based virtual screening is a versatile tool to discover ligands with tailored pharmacological properties.
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| 4. |
- Kampen, Stefanie, et al.
(författare)
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Structure-Guided Design of G-Protein-Coupled Receptor Polypharmacology
- 2021
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Ingår i: Angewandte Chemie International Edition. - : John Wiley & Sons. - 1433-7851 .- 1521-3773. ; 60:33, s. 18022-18030
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Matricon, Pierre, et al.
(författare)
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Structure-based virtual screening discovers potent and selective adenosine A1 receptor antagonists
- 2023
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 257
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Tidskriftsartikel (refereegranskat)abstract
- Development of subtype-selective leads is essential in drug discovery campaigns targeting G protein-coupled receptors (GPCRs). Herein, a structure-based virtual screening approach to rationally design subtype-selective ligands was applied to the A1 and A2A adenosine receptors (A1R and A2AR). Crystal structures of these closely related subtypes revealed a non-conserved subpocket in the binding sites that could be exploited to identify A1R selective ligands. A library of 4.6 million compounds was screened computationally against both receptors using molecular docking and 20 A1R selective ligands were predicted. Of these, seven antagonized the A1R with micromolar activities and several compounds displayed slight selectivity for this subtype. Twenty-seven analogs of two discovered scaffolds were designed, resulting in antagonists with nanomolar potency and up to 76-fold A1R-selectivity. Our results show the potential of structure-based virtual screening to guide discovery and optimization of subtype-selective ligands, which could facilitate the development of safer drugs.
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| 6. |
- Meyder, Agnes, et al.
(författare)
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StructureProfiler : an all-in-one tool for 3D protein structure profiling
- 2018
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 35:5, s. 874-876
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Tidskriftsartikel (refereegranskat)abstract
- Motivation Three-dimensional protein structures are important starting points for elucidating protein function and applications like drug design. Computational methods in this area rely on high quality validation datasets which are usually manually assembled. Due to the increase in published structures as well as the increasing demand for specially tailored validation datasets, automatic procedures should be adopted.Results StructureProfiler is a new tool for automatic, objective and customizable profiling of X-ray protein structures based on the most frequently applied selection criteria currently in use to assemble benchmark datasets. As examples, four dataset configurations (Astex, Iridium, Platinum, combined), all results of the combined tests and the list of all PDB Ids passing the combined criteria set are attached in the Supplementary Material.
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| 7. |
- Panel, Nicolas, et al.
(författare)
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Design of Drug Efficacy Guided by Free Energy Simulations of the β2-Adrenoceptor
- 2023
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Ingår i: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 62:22
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Tidskriftsartikel (refereegranskat)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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