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Performance of Virtual Screening against GPCR Homology Models: Impact of Template Selection and Treatment of Binding Site Plasticity.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.ORCID iD: 0000-0002-9229-5314
Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences of Pompeu Fabra University (UPF)–Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences of Pompeu Fabra University (UPF)–Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
(English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358Article in journal (Refereed) Submitted
Keywords [en]
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: urn:nbn:se:uu:diva-399135OAI: oai:DiVA.org:uu-399135DiVA, id: diva2:1378888
Available from: 2019-12-16 Created: 2019-12-16 Last updated: 2020-02-17Bibliographically approved
In thesis
1. New Paradigms in GPCR Drug Discovery: Structure Prediction and Design of Ligands with Tailored Properties
Open this publication in new window or tab >>New Paradigms in GPCR Drug Discovery: Structure Prediction and Design of Ligands with Tailored Properties
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
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:nbn:se:uu:diva-399133 (URN)978-91-513-0836-4 (ISBN)
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

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