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New Paradigms in GPCR Drug Discovery: Structure Prediction and Design of Ligands with Tailored Properties
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.ORCID iD: 0000-0002-9229-5314
2020 (English)Doctoral thesis, comprehensive summary (Other academic) [Artistic work]
Abstract [en]

G protein-coupled receptors (GPCRs) constitute a large superfamily of membrane proteins with key roles in cellular signaling. Upon activation by a ligand, GPCRs transduce signals from the extracellular to the intracellular environment. GPCRs are important drug targets and are associated with diseases such as central nervous system (CNS) disorders, cardiovascular diseases, cancer, and diabetes. Currently, 34% of FDA-approved drugs mediate their effects via modulation of GPCRs. Research during the past decades has resulted in a deeper understanding of GPCR structure and function. Moreover, recent breakthroughs in structural biology allowed the determination of several atomic resolution GPCR structures. New paradigms in GPCR pharmacology have also emerged that can lead to improved drugs. Together, these advances provide new avenues for structure-based drug discovery. The work in this thesis focused on how the large amount of structural data gathered over the last decades can be used to model GPCR targets for which no experimental structures are available, and the use of structure-based virtual screening (SBVS) campaigns to identify ligands with tailored pharmacological properties. In paper I, we investigated how template selection affects the virtual screening performance of homology models of the D2 dopamine receptor (D2R) and serotonin 5-HT2A receptor (5-HT2AR). In papers II and III, SBVS methods were used to identify dual inhibitors of the A2A adenosine receptor (A2AAR) and an enzyme, which could be relevant for treatment of Parkinson’s Disease, and functionally selective D2R ligands from a focused library. Finally, we also investigated how structural information can complement computational and biophysical methods to model and characterize the A2AAR-D2R heterodimer (paper IV).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. , p. 63
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1889
Keywords [en]
G Protein-Coupled Receptor, Molecular Docking, Virtual Screening, Homology Modeling, Molecular Dynamics Simulation, Chemical Library, Functionally Selective Ligand, Polypharmacology, Dimerization
National Category
Bioinformatics and Systems Biology Structural Biology
Research subject
Biology with specialization in Molecular Biotechnology
Identifiers
URN: urn:nbn:se:uu:diva-399133ISBN: 978-91-513-0836-4 (print)OAI: oai:DiVA.org:uu-399133DiVA, id: diva2:1378890
Public defence
2020-02-14, Room A1:111a, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2020-01-24 Created: 2019-12-16 Last updated: 2020-03-05Bibliographically approved
List of papers
1. Performance of Virtual Screening against GPCR Homology Models: Impact of Template Selection and Treatment of Binding Site Plasticity.
Open this publication in new window or tab >>Performance of Virtual Screening against GPCR Homology Models: Impact of Template Selection and Treatment of Binding Site Plasticity.
(English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358Article in journal (Refereed) Submitted
Keywords
G protein-coupled receptor, dopamine receptor, serotonin receptor, homology modeling, molecular docking, molecular dynamics simulation, virtual screening, computer-aided drug design
National Category
Bioinformatics and Systems Biology Structural Biology
Identifiers
urn:nbn:se:uu:diva-399135 (URN)
Available from: 2019-12-16 Created: 2019-12-16 Last updated: 2020-02-17Bibliographically approved
2. Docking Screens for Dual Inhibitors of Disparate Drug Targets for Parkinson's Disease
Open this publication in new window or tab >>Docking Screens for Dual Inhibitors of Disparate Drug Targets for Parkinson's Disease
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 12, p. 5269-5278Article in journal (Refereed) Published
Abstract [en]

Modulation of multiple biological targets with a single drug can lead to synergistic therapeutic effects and has been demonstrated to be essential for efficient treatment of CNS disorders. However, rational design of compounds that interact with several targets is very challenging. Here, we demonstrate that structure-based virtual screening can guide the discovery of multi-target ligands of unrelated proteins relevant for Parkinson's disease. A library with 5.4 million molecules was docked to crystal structures of the A(2A) adenosine receptor (A(2A)AR) and monoamine oxidase B (MAO-B). Twenty-four compounds that were among the highest ranked for both binding sites were evaluated experimentally, resulting in the discovery of four dual-target ligands. The most potent compound was an A(2A)AR antagonist with nanomolar affinity (K-i = 19 nM) and inhibited MAO-B with an IC50 of 100 nM. Optimization guided by the predicted binding modes led to the identification of a second potent dual-target scaffold. The two discovered scaffolds were shown to counteract 6-hydroxydopamine-induced neurotoxicity in dopaminergic neuronal-like SH-SY5Y cells. Structure-based screening can hence be used to identify ligands with specific polypharmacological profiles, providing new avenues for drug development against complex diseases.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-361114 (URN)10.1021/acs.jmedchem.8b00204 (DOI)000437811200015 ()29792714 (PubMedID)
Funder
EU, Horizon 2020, 715052Swedish Research Council, 2013-5708Swedish Research Council, 2017-4676Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-09-21 Created: 2018-09-21 Last updated: 2019-12-16Bibliographically approved
3. Structure-Guided Screening for Functionally Selective D-2 Dopamine Receptor Ligands from a Virtual Chemical Library
Open this publication in new window or tab >>Structure-Guided Screening for Functionally Selective D-2 Dopamine Receptor Ligands from a Virtual Chemical Library
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2017 (English)In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 12, no 10, p. 2652-2661Article in journal (Refereed) Published
Abstract [en]

Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D-2 dopamine receptor (D2R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D2R ligands was explored using structure-based virtual screening. Molecular docking of known functionally selective ligands to a D2R homology model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13-000 compounds bearing 2,3-dichlorophenylpiperazine, a privileged orthosteric scaffold, connected to diverse chemical moieties via a linker was docked to the D2R model. Eighteen top-ranked compounds that occupied both the orthosteric and allosteric site were synthesized, leading to the discovery of 16 partial agonists. A majority of the ligands had comparable maximum effects in the G protein and beta-arrestin recruitment assays, but a subset displayed preference for a single pathway. In particular, compound 4 stimulated beta-arrestin recruitment (EC50 = 320 nM, E-max = 16%) but had no detectable G protein signaling. The use of structure-based screening and virtual libraries to discover GPCR ligands with tailored functional properties will be discussed.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2017
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-340768 (URN)10.1021/acschembio.7b00493 (DOI)000413709700023 ()28846380 (PubMedID)
Funder
German Research Foundation (DFG)Swedish Research Council, 2013-5708Åke Wiberg Foundation, M15-0287Åke Wiberg Foundation, M16-0233
Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2019-12-16Bibliographically approved
4. Mapping the Interface of a GPCR Dimer: A Structural Model of the A(2A) Adenosine and D-2 Dopamine Receptor Heteromer
Open this publication in new window or tab >>Mapping the Interface of a GPCR Dimer: A Structural Model of the A(2A) Adenosine and D-2 Dopamine Receptor Heteromer
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2018 (English)In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 829Article in journal (Refereed) Published
Abstract [en]

The A(2A) adenosine (A(2A)R) and D-2 dopamine (D2R) receptors form oligomers in the cell membrane and allosteric interactions across the A(2A)R-D2R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of A(2A)R-D2R heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited. In this work, a structural model of the A(2A)R-D2R heterodimer was generated using a combined experimental and computational approach. Regions involved in the heteromer interface were modeled based on the effects of peptides derived from the transmembrane (TM) helices on A(2A)R-D2R receptor-receptor interactions in bioluminescence resonance energy transfer (BRET) and proximity ligation assays. Peptides corresponding to TM-IV and TM-V of the A(2A)R blocked heterodimer interactions and disrupted the allosteric effect of A(2A)R activation on D2R agonist binding. Protein-protein docking was used to construct a model of the A(2A)R-D2R heterodimer with a TM-IV/V interface, which was refined using molecular dynamics simulations. Mutations in the predicted interface reduced A(2A)R-D2R interactions in BRET experiments and altered the allosteric modulation. The heterodimer model provided insights into the structural basis of allosteric modulation and the technique developed to characterize the A(2A)R-D2R interface can be extended to study the many other G protein-coupled receptors that engage in heteroreceptor complexes.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2018
Keywords
G protein-coupled receptor, D-2 dopamine receptor, A(2A) adenosine receptor, heteroreceptor complex, dimerization, dimer interface, allosteric modulation
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-362490 (URN)10.3389/fphar.2018.00829 (DOI)000443127500001 ()30214407 (PubMedID)
Funder
Swedish Research Council, 2013-5708Swedish Research Council, 2017-4676Swedish Research CouncilÅke Wiberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceThe Swedish Brain Foundation
Available from: 2018-10-10 Created: 2018-10-10 Last updated: 2019-12-16Bibliographically approved

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