{"entity": "researcher", "timestamp": "2026-10-10T12:05:06.784Z", "family": "Jacobson", "given": "Kenneth A", "initials": "KA", "orcid": "0000-0001-8104-1493", "affiliations": ["Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Bethesda Maryland 20892 USA."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/9f89d80a5ce94ea5a4e02619526c833c.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/9f89d80a5ce94ea5a4e02619526c833c"}}, "publications": [{"entity": "publication", "iuid": "18ef8f8a2179462f9bed541815432282", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/18ef8f8a2179462f9bed541815432282.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/18ef8f8a2179462f9bed541815432282"}}, "title": "Adenosine A2A receptor antagonists: from caffeine to selective non-xanthines.", "authors": [{"family": "Jacobson", "given": "Kenneth A", "initials": "KA", "orcid": "0000-0001-8104-1493", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9f89d80a5ce94ea5a4e02619526c833c.json"}}, {"family": "Gao", "given": "Zhan-Guo", "initials": "ZG"}, {"family": "Matricon", "given": "Pierre", "initials": "P", "orcid": "0000-0001-9350-896X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/19dcd180ddc54eb48269a1638d83ece1.json"}}, {"family": "Eddy", "given": "Matthew T", "initials": "MT"}, {"family": "Carlsson", "given": "Jens", "initials": "J", "orcid": "0000-0003-4623-2977", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/792c1cd4aca248dc94b967115ffa82df.json"}}], "type": "journal article", "published": "2022-07-00", "journal": {"title": "Br J Pharmacol", "issn": "1476-5381", "volume": "179", "issue": "14", "pages": "3496-3511", "issn-l": null}, "abstract": "A long evolution of knowledge of the psychostimulant caffeine led in the 1960s to another purine natural product, adenosine and its A2A receptor. Adenosine is a short-lived autocrine/paracrine mediator that acts pharmacologically at four different adenosine receptors in a manner opposite to the pan-antagonist caffeine and serves as an endogenous allostatic regulator. Although detrimental in the developing brain, caffeine appears to be cerebroprotective in aging. Moderate caffeine consumption in adults, except in pregnancy, may also provide benefit in pain, diabetes, and kidney and liver disorders. Inhibition of A2A receptors is one of caffeine's principal effects and we now understand this interaction at the atomic level. The A2A receptor has become a prototypical example of utilizing high-resolution structures of GPCRs for the rational design of chemically diverse drug molecules. The previous focus on discovery of selective A2A receptor antagonists for neurodegenerative diseases has expanded to include immunotherapy for cancer, and clinical trials have ensued. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.", "doi": "10.1111/bph.15103", "pmid": "32424811", "labels": {"SciLifeLab Fellow": "", "Jens Carlsson": ""}, "xrefs": [{"db": "mid", "key": "NIHMS1818154"}, {"db": "pmc", "key": "PMC9251831"}], "notes": [], "created": "2022-11-07T16:31:06.078Z", "modified": "2026-09-23T07:38:42.604Z"}, {"entity": "publication", "iuid": "bd1311f86a834eb7aef12cc72dd75f69", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/bd1311f86a834eb7aef12cc72dd75f69.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/bd1311f86a834eb7aef12cc72dd75f69"}}, "title": "Fragment-based design of selective GPCR ligands guided by free energy simulations.", "authors": [{"family": "Matricon", "given": "Pierre", "initials": "P", "orcid": "0000-0001-9350-896X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/19dcd180ddc54eb48269a1638d83ece1.json"}}, {"family": "Vo", "given": "Duc Duy", "initials": "DD"}, {"family": "Gao", "given": "Zhan-Guo", "initials": "ZG"}, {"family": "Kihlberg", "given": "Jan", "initials": "J", "orcid": "0000-0002-4205-6040", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7edb4dfa7c4b4d6c8c4cf0282a9c9a1a.json"}}, {"family": "Jacobson", "given": "Kenneth A", "initials": "KA", "orcid": "0000-0001-8104-1493", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9f89d80a5ce94ea5a4e02619526c833c.json"}}, {"family": "Carlsson", "given": "Jens", "initials": "J", "orcid": "0000-0003-4623-2977", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/792c1cd4aca248dc94b967115ffa82df.json"}}], "type": "journal article", "published": "2021-11-19", "journal": {"title": "Chem. Commun. (Camb.)", "issn": "1364-548X", "volume": "57", "issue": "92", "pages": "12305-12308", "issn-l": "1359-7345"}, "abstract": "Fragment-based drug discovery relies on successful optimization of weakly binding ligands for affinity and selectivity. Herein, we explored strategies for structure-based evolution of fragments binding to a G protein-coupled receptor. Molecular dynamics simulations combined with rigorous free energy calculations guided synthesis of nanomolar ligands with up to >1000-fold improvements of binding affinity and close to 40-fold subtype selectivity.", "doi": "10.1039/d1cc03202j", "pmid": "34734588", "labels": {"Jens Carlsson": "", "SciLifeLab Fellow": ""}, "xrefs": [{"db": "mid", "key": "NIHMS1758126"}, {"db": "pmc", "key": "PMC8603191"}], "notes": [], "created": "2021-12-05T12:22:49.128Z", "modified": "2026-09-23T11:03:13.483Z"}, {"entity": "publication", "iuid": "a63318156f0a4261b5e97b0cde88a96e", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/a63318156f0a4261b5e97b0cde88a96e.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/a63318156f0a4261b5e97b0cde88a96e"}}, "title": "Ligand design by targeting a binding site water.", "authors": [{"family": "Matricon", "given": "Pierre", "initials": "P", "orcid": "0000-0001-9350-896X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/19dcd180ddc54eb48269a1638d83ece1.json"}}, {"family": "Suresh", "given": "R Rama", "initials": "RR", "orcid": "0000-0001-7693-3681", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/704e3b2e2f3948b4808785855b3516dd.json"}}, {"family": "Gao", "given": "Zhan-Guo", "initials": "ZG"}, {"family": "Panel", "given": "Nicolas", "initials": "N"}, {"family": "Jacobson", "given": "Kenneth A", "initials": "KA", "orcid": "0000-0001-8104-1493", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9f89d80a5ce94ea5a4e02619526c833c.json"}}, {"family": "Carlsson", "given": "Jens", "initials": "J"}], "type": "journal article", "published": "2020-11-19", "journal": {"title": "Chem Sci", "issn": "2041-6520", "issn-l": null, "volume": "12", "issue": "3", "pages": "960-968"}, "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.", "doi": "10.1039/d0sc04938g", "pmid": "34163862", "labels": {"Jens Carlsson": "", "SciLifeLab Fellow": ""}, "xrefs": [{"db": "pmc", "key": "PMC8179138"}, {"db": "pii", "key": "d0sc04938g"}], "notes": [], "created": "2020-11-30T18:42:43.554Z", "modified": "2026-09-23T08:35:30.513Z"}, {"entity": "publication", "iuid": "869071673ef84f6787a21f7a45e96f87", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/869071673ef84f6787a21f7a45e96f87.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/869071673ef84f6787a21f7a45e96f87"}}, "title": "Fragment optimization for GPCRs by molecular dynamics free energy calculations: Probing druggable subpockets of the A 2A adenosine receptor binding site.", "authors": [{"family": "Matricon", "given": "Pierre", "initials": "P", "orcid": "0000-0001-9350-896X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/19dcd180ddc54eb48269a1638d83ece1.json"}}, {"family": "Ranganathan", "given": "Anirudh", "initials": "A"}, {"family": "Warnick", "given": "Eugene", "initials": "E"}, {"family": "Gao", "given": "Zhan-Guo", "initials": "ZG"}, {"family": "Rudling", "given": "Axel", "initials": "A"}, {"family": "Lambertucci", "given": "Catia", "initials": "C"}, {"family": "Marucci", "given": "Gabriella", "initials": "G"}, {"family": "Ezzati", "given": "Aitakin", "initials": "A"}, {"family": "Jaiteh", "given": "Mariama", "initials": "M"}, {"family": "Dal Ben", "given": "Diego", "initials": "D", "orcid": "0000-0002-6616-6885", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/441223ecb54d428c8d310de9963d8683.json"}}, {"family": "Jacobson", "given": "Kenneth A", "initials": "KA", "orcid": "0000-0001-8104-1493", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9f89d80a5ce94ea5a4e02619526c833c.json"}}, {"family": "Carlsson", "given": "Jens", "initials": "J"}], "type": "journal article", "published": "2017-07-25", "journal": {"title": "Sci Rep", "issn": "2045-2322", "issn-l": "2045-2322", "volume": "7", "issue": "1", "pages": "6398"}, "abstract": "Fragment-based lead discovery is becoming an increasingly popular strategy for drug discovery. Fragment screening identifies weakly binding compounds that require optimization to become high-affinity leads. As design of leads from fragments is challenging, reliable computational methods to guide optimization would be invaluable. We evaluated using molecular dynamics simulations and the free energy perturbation method (MD/FEP) in fragment optimization for the A2A adenosine receptor, a pharmaceutically relevant G protein-coupled receptor. Optimization of fragments exploring two binding site subpockets was probed by calculating relative binding affinities for 23 adenine derivatives, resulting in strong agreement with experimental data (R2 = 0.78). The predictive power of MD/FEP was significantly better than that of an empirical scoring function. We also demonstrated the potential of the MD/FEP to assess multiple binding modes and to tailor the thermodynamic profile of ligands during optimization. Finally, MD/FEP was applied prospectively to optimize three nonpurine fragments, and predictions for 12 compounds were evaluated experimentally. The direction of the change in binding affinity was correctly predicted in a majority of the cases, and agreement with experiment could be improved with rigorous parameter derivation. The results suggest that MD/FEP will become a powerful tool in structure-driven optimization of fragments to lead candidates.", "doi": "10.1038/s41598-017-04905-0", "pmid": "28743961", "labels": {"Affiliated researcher": "", "Jens Carlsson": "", "SciLifeLab Fellow": ""}, "xrefs": [{"db": "pmc", "key": "PMC5526870"}, {"db": "pii", "key": "10.1038/s41598-017-04905-0"}], "notes": [], "created": "2018-12-03T14:43:43.770Z", "modified": "2026-09-23T08:37:38.998Z"}]}