{"entity": "researcher", "timestamp": "2026-08-13T19:08:38.279Z", "family": "Carlsson", "given": "Jens", "initials": "J", "orcid": "0000-0003-4623-2977", "affiliations": ["Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, SE-75124 Uppsala, Sweden"], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/d7d91087358e46e38bb1b7110dc0b214.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/d7d91087358e46e38bb1b7110dc0b214"}}, "publications": [{"entity": "publication", "iuid": "023ffcdeef6f4cfdb03af2b67df53148", "links": {"self": {"href": "https://publications.scilifelab.se/publication/023ffcdeef6f4cfdb03af2b67df53148.json"}, "display": {"href": "https://publications.scilifelab.se/publication/023ffcdeef6f4cfdb03af2b67df53148"}}, "title": "Docking of virtual libraries identifies small-molecule agonists of neurotensin receptors with analgesic activity.", "authors": [{"family": "Panel", "given": "Nicolas", "initials": "N", "orcid": "0000-0001-8782-0586", "researcher": {"href": "https://publications.scilifelab.se/researcher/24a74eba4e5c4234b0f21675c2294f04.json"}}, {"family": "Vo", "given": "Duy Duc", "initials": "DD"}, {"family": "H\u00fcbner", "given": "Harald", "initials": "H", "orcid": "0000-0002-7892-599X", "researcher": {"href": "https://publications.scilifelab.se/researcher/76a33c1eae424518885794e3a10bec3a.json"}}, {"family": "Deluigi", "given": "Mattia", "initials": "M", "orcid": "0000-0001-9132-2774", "researcher": {"href": "https://publications.scilifelab.se/researcher/d69b69c3083b4edaa151460909d09d52.json"}}, {"family": "Pach", "given": "Szymon", "initials": "S", "orcid": "0000-0001-6109-7123", "researcher": {"href": "https://publications.scilifelab.se/researcher/0549d10cbdc24117a6ae0d0a10617674.json"}}, {"family": "B\u00e9lair", "given": "F\u00e9lix", "initials": "F"}, {"family": "Weikert", "given": "Dorothee", "initials": "D", "orcid": "0000-0003-2259-9002", "researcher": {"href": "https://publications.scilifelab.se/researcher/9a665be80cf94398b96c3797ba324815.json"}}, {"family": "Klenk", "given": "Christoph", "initials": "C", "orcid": "0000-0001-5199-7144", "researcher": {"href": "https://publications.scilifelab.se/researcher/bf7a1da857fb403bb9c8c5309f3c4f4e.json"}}, {"family": "Hilge", "given": "Mark", "initials": "M"}, {"family": "Shiva", "given": "Niharika", "initials": "N", "orcid": "0009-0007-7951-4598", "researcher": {"href": "https://publications.scilifelab.se/researcher/2af9534c74134de3b743ed89b01d0a2b.json"}}, {"family": "Brochu", "given": "Isabelle", "initials": "I"}, {"family": "Longpr\u00e9", "given": "Jean-Michel", "initials": "JM", "orcid": "0000-0003-3985-2318", "researcher": {"href": "https://publications.scilifelab.se/researcher/eff617d76bd14603a193a60591e3000d.json"}}, {"family": "B\u00e4llgren", "given": "Frida", "initials": "F", "orcid": "0009-0007-4885-9120", "researcher": {"href": "https://publications.scilifelab.se/researcher/911997685ed347199dbf0b870df849ea.json"}}, {"family": "Saleh", "given": "Aljona", "initials": "A", "orcid": "0009-0002-2121-043X", "researcher": {"href": "https://publications.scilifelab.se/researcher/c469c0a07dc746c2a16b122c2269480c.json"}}, {"family": "Hu", "given": "Huabin", "initials": "H"}, {"family": "Kapla", "given": "Jon", "initials": "J", "orcid": "0000-0003-3328-1921", "researcher": {"href": "https://publications.scilifelab.se/researcher/f6f10ed4144348d59541a02d6e17daa2.json"}}, {"family": "Kampen", "given": "Stefanie", "initials": "S"}, {"family": "Cabeza de Vaca", "given": "Israel", "initials": "I", "orcid": "0000-0002-6208-1091", "researcher": {"href": "https://publications.scilifelab.se/researcher/65628edbdaa448b8ab37d5eb4e100aee.json"}}, {"family": "Kihlberg", "given": "Jan", "initials": "J", "orcid": "0000-0002-4205-6040", "researcher": {"href": "https://publications.scilifelab.se/researcher/f9805d4f39cc48f79a6e6ba076917021.json"}}, {"family": "Wettschureck", "given": "Nina", "initials": "N", "orcid": "0000-0001-6858-1460", "researcher": {"href": "https://publications.scilifelab.se/researcher/aa8eab17eed54b85a233fe74447556a8.json"}}, {"family": "Sarret", "given": "Philippe", "initials": "P", "orcid": "0000-0002-7627-701X", "researcher": {"href": "https://publications.scilifelab.se/researcher/4511aa2978af482ab9492f01c521b5bd.json"}}, {"family": "Pl\u00fcckthun", "given": "Andreas", "initials": "A", "orcid": "0000-0003-4191-5306", "researcher": {"href": "https://publications.scilifelab.se/researcher/3f67a65bf469443a89665bd244bfd0f7.json"}}, {"family": "Gmeiner", "given": "Peter", "initials": "P", "orcid": "0000-0002-4127-197X", "researcher": {"href": "https://publications.scilifelab.se/researcher/8385c6b025fe40e7b8e2f4855625a666.json"}}, {"family": "Carlsson", "given": "Jens", "initials": "J", "orcid": "0000-0003-4623-2977", "researcher": {"href": "https://publications.scilifelab.se/researcher/d7d91087358e46e38bb1b7110dc0b214.json"}}], "type": "journal article", "published": "2026-07-22", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "17", "issue": "1", "issn-l": "2041-1723"}, "abstract": "Peptide-activated G protein-coupled receptors (GPCRs) play crucial roles in numerous diseases, but remain difficult therapeutic targets due to the challenges in developing small-molecule drugs. Here, we explore structure-based strategies to identify small-molecule agonists of neurotensin (NTS) receptors, which hold promise for developing non-opioid analgesics. Chemical libraries of drug-like molecules are first designed based on a receptor-peptide complex, and then 14.5 million compounds are computationally docked to the orthosteric binding site of the NTS1 receptor. A set of 39 top-ranked compounds is synthesized, and seven of these are experimentally confirmed to activate the NTS1 receptor. Structure-guided optimization yields NTS1 ligands with signaling signatures distinct from the endogenous peptide, and these compounds also exhibit high affinity for the NTS2 receptor. High-resolution crystal structures of two agonists bound to the NTS1 receptor confirm predicted binding modes and reveal key determinants of activation. In vivo, the compounds produce robust antinociception in rodents without inducing hypotension, consistent with a contribution of NTS2 receptor activity. To facilitate broader application of our virtual screening approach to peptide-binding GPCRs, we provide access to tailored chemical libraries containing billions of readily synthesizable compounds.", "doi": "10.1038/s41467-026-74990-1", "pmid": "42486867", "labels": {"Drug Discovery and Development": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC13392031"}, {"db": "pii", "key": "10.1038/s41467-026-74990-1"}], "notes": [], "created": "2026-08-04T11:59:25.332Z", "modified": "2026-08-04T11:59:29.136Z"}, {"entity": "publication", "iuid": "310db69525be40ed9f4e569c00320568", "links": {"self": {"href": "https://publications.scilifelab.se/publication/310db69525be40ed9f4e569c00320568.json"}, "display": {"href": "https://publications.scilifelab.se/publication/310db69525be40ed9f4e569c00320568"}}, "title": "Ultra-large virtual screening unveils potent agonists of the neuromodulatory orphan receptor GPR139.", "authors": [{"family": "Cabeza de Vaca", "given": "Israel", "initials": "I", "orcid": "0000-0002-6208-1091", "researcher": {"href": "https://publications.scilifelab.se/researcher/65628edbdaa448b8ab37d5eb4e100aee.json"}}, {"family": "Trapkov", "given": "Boris", "initials": "B", "orcid": "0000-0003-1245-888X", "researcher": {"href": "https://publications.scilifelab.se/researcher/6dc796a7e85b4849ae92b2d3ce13a885.json"}}, {"family": "Shen", "given": "Ling", "initials": "L"}, {"family": "Vo", "given": "Duy Duc", "initials": "DD"}, {"family": "Zhang", "given": "Xiaoqun", "initials": "X", "orcid": "0000-0002-9461-8682", "researcher": {"href": "https://publications.scilifelab.se/researcher/4f307c88103d43b1b0b893fa59a8e828.json"}}, {"family": "Yang", "given": "Yunting", "initials": "Y"}, {"family": "Pezeshki", "given": "Mitra", "initials": "M", "orcid": "0009-0001-0155-7463", "researcher": {"href": "https://publications.scilifelab.se/researcher/e51c7fe034b9477996d92c2dbddf6f21.json"}}, {"family": "Zhang", "given": "Xuehan", "initials": "X"}, {"family": "B\u00e4llgren", "given": "Frida", "initials": "F"}, {"family": "Saleh", "given": "Aljona", "initials": "A"}, {"family": "Tarnovskiy", "given": "Andrii V", "initials": "AV"}, {"family": "Radchenko", "given": "Dmytro S", "initials": "DS", "orcid": "0000-0001-5444-7754", "researcher": {"href": "https://publications.scilifelab.se/researcher/df4077c366bc4f4a8b422762c0be9cfe.json"}}, {"family": "Moroz", "given": "Yurii S", "initials": "YS", "orcid": "0000-0001-6073-002X", "researcher": {"href": "https://publications.scilifelab.se/researcher/4f8586d3b69b4782bed34192411a02e5.json"}}, {"family": "Br\u00e4uner-Osborne", "given": "Hans", "initials": "H"}, {"family": "Svenningsson", "given": "Per", "initials": "P", "orcid": "0000-0001-6727-3802", "researcher": {"href": "https://publications.scilifelab.se/researcher/5199496295334771ba3c5621a83a6f43.json"}}, {"family": "Kihlberg", "given": "Jan", "initials": "J", "orcid": "0000-0002-4205-6040", "researcher": {"href": "https://publications.scilifelab.se/researcher/f9805d4f39cc48f79a6e6ba076917021.json"}}, {"family": "Liu", "given": "Zhi-Jie", "initials": "ZJ", "orcid": "0000-0001-7279-2893", "researcher": {"href": "https://publications.scilifelab.se/researcher/bd5198c9a2924467bb85b451b99f381b.json"}}, {"family": "Hauser", "given": "Alexander Sebastian", "initials": "AS", "orcid": "0000-0003-1098-6419", "researcher": {"href": "https://publications.scilifelab.se/researcher/0d10bc754dbc4fb49ae26994ab9fcff1.json"}}, {"family": "Carlsson", "given": "Jens", "initials": "J", "orcid": "0000-0003-4623-2977", "researcher": {"href": "https://publications.scilifelab.se/researcher/d7d91087358e46e38bb1b7110dc0b214.json"}}], "type": "journal article", "published": "2025-12-09", "journal": {"title": "Nat Commun", "issn": "2041-1723", "issn-l": "2041-1723"}, "abstract": "The orphan G protein-coupled receptor (GPCR) GPR139 attracts interest as a target for neuropsychiatric disorders. Whereas the physiological functions of GPR139 remain elusive, a high-resolution receptor structure is now available. To assess whether structural information enables ligand discovery, we computationally dock 235 million compounds to the GPR139 binding site. Of 68 top-ranked compounds evaluated experimentally, five are full agonists with potencies ranging from 160 nM to 3.6 \u00b5M. Structure-guided optimization identifies one of the most potent GPR139 agonists, and a cryo-EM structure of the receptor-ligand complex confirms the predicted binding mode. Functional characterization provides insights into GPR139 signalling, and one agonist elicits behavioural effects in mice. We also explore the potential to replace experimental structure determination with the deep-learning method AlphaFold3, revealing a limited capability of artificial intelligence to model receptor-ligand interactions for understudied GPCRs. The results demonstrate how high-resolution GPCR structures combined with large-library docking can accelerate drug discovery.", "doi": "10.1038/s41467-025-66845-y", "pmid": "41365886", "labels": {"Drug Discovery and Development": "Service"}, "xrefs": [{"db": "pii", "key": "10.1038/s41467-025-66845-y"}], "notes": [], "created": "2025-12-15T10:13:02.964Z", "modified": "2025-12-15T10:13:04.219Z"}, {"entity": "publication", "iuid": "33f7c1d27c724a188e43c1e941c7eaac", "links": {"self": {"href": "https://publications.scilifelab.se/publication/33f7c1d27c724a188e43c1e941c7eaac.json"}, "display": {"href": "https://publications.scilifelab.se/publication/33f7c1d27c724a188e43c1e941c7eaac"}}, "title": "Rapid traversal of vast chemical space using machine learning-guided docking screens.", "authors": [{"family": "Luttens", "given": "Andreas", "initials": "A", "orcid": "0000-0003-2915-7901", "researcher": {"href": "https://publications.scilifelab.se/researcher/7d46047fab4247caaeecf31be6da987f.json"}}, {"family": "Cabeza de Vaca", "given": "Israel", "initials": "I"}, {"family": "Sparring", "given": "Leonard", "initials": "L"}, {"family": "Brea", "given": "Jos\u00e9", "initials": "J"}, {"family": "Mart\u00ednez", "given": "Ant\u00f3n Leandro", "initials": "AL", "orcid": "0000-0002-1595-3459", "researcher": {"href": "https://publications.scilifelab.se/researcher/46b781fca7af46b49699abf9f063c390.json"}}, {"family": "Kahlous", "given": "Nour Aldin", "initials": "NA", "orcid": "0000-0002-7744-1491", "researcher": {"href": "https://publications.scilifelab.se/researcher/f7e3d259da7a4b6d97973a0de8b3d497.json"}}, {"family": "Radchenko", "given": "Dmytro S", "initials": "DS", "orcid": "0000-0001-5444-7754", "researcher": {"href": "https://publications.scilifelab.se/researcher/df4077c366bc4f4a8b422762c0be9cfe.json"}}, {"family": "Moroz", "given": "Yurii S", "initials": "YS", "orcid": "0000-0001-6073-002X", "researcher": {"href": "https://publications.scilifelab.se/researcher/4f8586d3b69b4782bed34192411a02e5.json"}}, {"family": "Loza", "given": "Mar\u00eda Isabel", "initials": "MI", "orcid": "0000-0003-4730-0863", "researcher": {"href": "https://publications.scilifelab.se/researcher/16ba410826ea43aaa8e14e8bb14e6fac.json"}}, {"family": "Norinder", "given": "Ulf", "initials": "U", "orcid": "0000-0003-3107-331X", "researcher": {"href": "https://publications.scilifelab.se/researcher/ecd436012ccc4e29bd07b730fbda51c3.json"}}, {"family": "Carlsson", "given": "Jens", "initials": "J", "orcid": "0000-0003-4623-2977", "researcher": {"href": "https://publications.scilifelab.se/researcher/d7d91087358e46e38bb1b7110dc0b214.json"}}], "type": "journal article", "published": "2025-04-00", "journal": {"title": "Nat Comput Sci", "issn": "2662-8457", "volume": "5", "issue": "4", "pages": "301-312", "issn-l": null}, "abstract": "The accelerating growth of make-on-demand chemical libraries provides unprecedented opportunities to identify starting points for drug discovery with virtual screening. However, these multi-billion-scale libraries are challenging to screen, even for the fastest structure-based docking methods. Here we explore a strategy that combines machine learning and molecular docking to enable rapid virtual screening of databases containing billions of compounds. In our workflow, a classification algorithm is trained to identify top-scoring compounds based on molecular docking of 1 million compounds to the target protein. The conformal prediction framework is then used to make selections from the multi-billion-scale library, reducing the number of compounds to be scored by docking. The CatBoost classifier showed an optimal balance between speed and accuracy and was used to adapt the workflow for screens of ultralarge libraries. Application to a library of 3.5 billion compounds demonstrated that our protocol can reduce the computational cost of structure-based virtual screening by more than 1,000-fold. Experimental testing of predictions identified ligands of G protein-coupled receptors and demonstrated that our approach enables discovery of compounds with multi-target activity tailored for therapeutic effect.", "doi": "10.1038/s43588-025-00777-x", "pmid": "40082701", "labels": {"Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC12021657"}, {"db": "pii", "key": "10.1038/s43588-025-00777-x"}], "notes": [], "created": "2025-11-28T10:47:46.133Z", "modified": "2025-11-28T10:47:46.396Z"}, {"entity": "publication", "iuid": "374916d5866340bd9a5d6c4801db1717", "links": {"self": {"href": "https://publications.scilifelab.se/publication/374916d5866340bd9a5d6c4801db1717.json"}, "display": {"href": "https://publications.scilifelab.se/publication/374916d5866340bd9a5d6c4801db1717"}}, "title": "Virtual fragment screening for DNA repair inhibitors in vast chemical space.", "authors": [{"family": "Luttens", "given": "Andreas", "initials": "A", "orcid": "0000-0003-2915-7901", "researcher": {"href": "https://publications.scilifelab.se/researcher/7d46047fab4247caaeecf31be6da987f.json"}}, {"family": "Vo", "given": "Duc Duy", "initials": "DD"}, {"family": "Scaletti", "given": "Emma R", "initials": "ER"}, {"family": "Wiita", "given": "Elis\u00e9e", "initials": "E"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Wallner", "given": "Olov", "initials": "O"}, {"family": "Davies", "given": "Jonathan", "initials": "J"}, {"family": "Ko\u0161enina", "given": "Sara", "initials": "S", "orcid": "0000-0001-7893-0249", "researcher": {"href": "https://publications.scilifelab.se/researcher/9370d4ecf19c438bb205c43c23f94f26.json"}}, {"family": "Meng", "given": "Liuzhen", "initials": "L"}, {"family": "Long", "given": "Maeve", "initials": "M"}, {"family": "Mortusewicz", "given": "Oliver", "initials": "O", "orcid": "0000-0002-4290-4994", "researcher": {"href": "https://publications.scilifelab.se/researcher/b62a88fc39a54906a40e28e679c9f624.json"}}, {"family": "Masuyer", "given": "Geoffrey", "initials": "G", "orcid": "0000-0002-9527-2310", "researcher": {"href": "https://publications.scilifelab.se/researcher/41dcc0806dba4a56bb04725812f3a000.json"}}, {"family": "Ballante", "given": "Flavio", "initials": "F", "orcid": "0000-0002-4831-3423", "researcher": {"href": "https://publications.scilifelab.se/researcher/20429d2a46f4479a9c262875794a3a9d.json"}}, {"family": "Michel", "given": "Maurice", "initials": "M"}, {"family": "Homan", "given": "Evert", "initials": "E"}, {"family": "Scobie", "given": "Martin", "initials": "M"}, {"family": "Kalder\u00e9n", "given": "Christina", "initials": "C"}, {"family": "Warpman Berglund", "given": "Ulrika", "initials": "U"}, {"family": "Tarnovskiy", "given": "Andrii V", "initials": "AV"}, {"family": "Radchenko", "given": "Dmytro S", "initials": "DS", "orcid": "0000-0001-5444-7754", "researcher": {"href": "https://publications.scilifelab.se/researcher/df4077c366bc4f4a8b422762c0be9cfe.json"}}, {"family": "Moroz", "given": "Yurii S", "initials": "YS", "orcid": "0000-0001-6073-002X", "researcher": {"href": "https://publications.scilifelab.se/researcher/4f8586d3b69b4782bed34192411a02e5.json"}}, {"family": "Kihlberg", "given": "Jan", "initials": "J", "orcid": "0000-0002-4205-6040", "researcher": {"href": "https://publications.scilifelab.se/researcher/f9805d4f39cc48f79a6e6ba076917021.json"}}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications.scilifelab.se/researcher/d97eba9f5edf4d76a5259c4baa8366c5.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T"}, {"family": "Carlsson", "given": "Jens", "initials": "J", "orcid": "0000-0003-4623-2977", "researcher": {"href": "https://publications.scilifelab.se/researcher/d7d91087358e46e38bb1b7110dc0b214.json"}}], "type": "journal article", "published": "2025-02-18", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "16", "issue": "1", "pages": "1741", "issn-l": "2041-1723"}, "abstract": "Fragment-based screening can catalyze drug discovery by identifying novel scaffolds, but this approach is limited by the small chemical libraries studied by biophysical experiments and the challenging optimization process. To expand the explored chemical space, we employ structure-based docking to evaluate orders-of-magnitude larger libraries than those used in traditional fragment screening. We computationally dock a set of 14 million fragments to 8-oxoguanine DNA glycosylase (OGG1), a difficult drug target involved in cancer and inflammation, and evaluate 29 highly ranked compounds experimentally. Four of these bind to OGG1 and X-ray crystallography confirms the binding modes predicted by docking. Furthermore, we show how fragment elaboration using searches among billions of readily synthesizable compounds identifies submicromolar inhibitors with anti-inflammatory and anti-cancer effects in cells. Comparisons of virtual screening strategies to explore a chemical space of 1022 compounds illustrate that fragment-based design enables enumeration of all molecules relevant for inhibitor discovery. Virtual fragment screening is hence a highly efficient strategy for navigating the rapidly growing combinatorial libraries and can serve as a powerful tool to accelerate drug discovery efforts for challenging therapeutic targets.", "doi": "10.1038/s41467-025-56893-9", "pmid": "39966348", "labels": {"Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11836371"}, {"db": "pii", "key": "10.1038/s41467-025-56893-9"}], "notes": [], "created": "2025-11-28T10:45:18.822Z", "modified": "2025-11-28T10:45:19.246Z"}, {"entity": "publication", "iuid": "4e32b1a69fb9494d8f947125c273d792", "links": {"self": {"href": "https://publications.scilifelab.se/publication/4e32b1a69fb9494d8f947125c273d792.json"}, "display": {"href": "https://publications.scilifelab.se/publication/4e32b1a69fb9494d8f947125c273d792"}}, "title": "AlphaFold accelerated discovery of psychotropic agonists targeting the trace amine-associated receptor 1.", "authors": [{"family": "D\u00edaz-Holgu\u00edn", "given": "Alejandro", "initials": "A", "orcid": "0000-0002-3449-5086", "researcher": {"href": "https://publications.scilifelab.se/researcher/335c8b7a0b6043fc984a1d21b77f721b.json"}}, {"family": "Saarinen", "given": "Marcus", "initials": "M"}, {"family": "Vo", "given": "Duc Duy", "initials": "DD"}, {"family": "Sturchio", "given": "Andrea", "initials": "A"}, {"family": "Branzell", "given": "Niclas", "initials": "N"}, {"family": "Cabeza de Vaca", "given": "Israel", "initials": "I", "orcid": "0000-0002-6208-1091", "researcher": {"href": "https://publications.scilifelab.se/researcher/65628edbdaa448b8ab37d5eb4e100aee.json"}}, {"family": "Hu", "given": "Huabin", "initials": "H"}, {"family": "Mitjavila-Dom\u00e8nech", "given": "N\u00faria", "initials": "N"}, {"family": "Lindqvist", "given": "Annika", "initials": "A", "orcid": "0009-0003-2587-8434", "researcher": {"href": "https://publications.scilifelab.se/researcher/f6e7610970e64dcba383e49b60df4f50.json"}}, {"family": "Baranczewski", "given": "Pawel", "initials": "P", "orcid": "0000-0001-5772-6791", "researcher": {"href": "https://publications.scilifelab.se/researcher/47f7af2466c14275a42aad4a431b2dcb.json"}}, {"family": "Millan", "given": "Mark J", "initials": "MJ"}, {"family": "Yang", "given": "Yunting", "initials": "Y", "orcid": "0000-0001-5700-1547", "researcher": {"href": "https://publications.scilifelab.se/researcher/5f8478fd3a4d4a2c8280843835b543d9.json"}}, {"family": "Carlsson", "given": "Jens", "initials": "J", "orcid": "0000-0003-4623-2977", "researcher": {"href": "https://publications.scilifelab.se/researcher/d7d91087358e46e38bb1b7110dc0b214.json"}}, {"family": "Svenningsson", "given": "Per", "initials": "P", "orcid": "0000-0001-6727-3802", "researcher": {"href": "https://publications.scilifelab.se/researcher/5199496295334771ba3c5621a83a6f43.json"}}], "type": "journal article", "published": "2024-08-09", "journal": {"title": "Sci Adv", "issn": "2375-2548", "volume": "10", "issue": "32", "pages": "eadn1524", "issn-l": "2375-2548"}, "abstract": "Artificial intelligence is revolutionizing protein structure prediction, providing unprecedented opportunities for drug design. To assess the potential impact on ligand discovery, we compared virtual screens using protein structures generated by the AlphaFold machine learning method and traditional homology modeling. More than 16 million compounds were docked to models of the trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor of unknown structure and target for treating neuropsychiatric disorders. Sets of 30 and 32 highly ranked compounds from the AlphaFold and homology model screens, respectively, were experimentally evaluated. Of these, 25 were TAAR1 agonists with potencies ranging from 12 to 0.03 \u03bcM. The AlphaFold screen yielded a more than twofold higher hit rate (60%) than the homology model and discovered the most potent agonists. A TAAR1 agonist with a promising selectivity profile and drug-like properties showed physiological and antipsychotic-like effects in wild-type but not in TAAR1 knockout mice. These results demonstrate that AlphaFold structures can accelerate drug discovery.", "doi": "10.1126/sciadv.adn1524", "pmid": "39110804", "labels": {"Chemical Biology Consortium Sweden": "Service", "Drug Discovery and Development": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11305387"}], "notes": [], "created": "2024-08-16T12:19:56.237Z", "modified": "2025-10-17T13:05:07.343Z"}, {"entity": "publication", "iuid": "7628290a41184ddf88a208637257ac06", "links": {"self": {"href": "https://publications.scilifelab.se/publication/7628290a41184ddf88a208637257ac06.json"}, "display": {"href": "https://publications.scilifelab.se/publication/7628290a41184ddf88a208637257ac06"}}, "title": "Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses.", "authors": [{"family": "Luttens", "given": "Andreas", "initials": "A", "orcid": "0000-0003-2915-7901", "researcher": {"href": "https://publications.scilifelab.se/researcher/7d46047fab4247caaeecf31be6da987f.json"}}, {"family": "Gullberg", "given": "Hjalmar", "initials": "H"}, {"family": "Abdurakhmanov", "given": "Eldar", "initials": "E"}, {"family": "Vo", "given": "Duy Duc", "initials": "DD"}, {"family": "Akaberi", "given": "Dario", "initials": "D", "orcid": "0000-0002-9595-9796", "researcher": {"href": "https://publications.scilifelab.se/researcher/4f2dffc1327b471fa84256a7837344f1.json"}}, {"family": "Talibov", "given": "Vladimir O", "initials": "VO"}, {"family": "Nekhotiaeva", "given": "Natalia", "initials": "N"}, {"family": "Vangeel", "given": "Laura", "initials": "L"}, {"family": "De Jonghe", "given": "Steven", "initials": "S", "orcid": "0000-0002-3872-6558", "researcher": {"href": "https://publications.scilifelab.se/researcher/3fbacfdaac194a87b975bf65cab9bfc4.json"}}, {"family": "Jochmans", "given": "Dirk", "initials": "D"}, {"family": "Krambrich", "given": "Janina", "initials": "J"}, {"family": "Tas", "given": "Ali", "initials": "A"}, {"family": "Lundgren", "given": "Bo", "initials": "B"}, {"family": "Gravenfors", "given": "Ylva", "initials": "Y", "orcid": "0000-0001-6025-4908", "researcher": {"href": "https://publications.scilifelab.se/researcher/deff200706ca4ee4be00bb8122de0c7b.json"}}, {"family": "Craig", "given": "Alexander J", "initials": "AJ"}, {"family": "Atilaw", "given": "Yoseph", "initials": "Y"}, {"family": "Sandstr\u00f6m", "given": "Anja", "initials": "A"}, {"family": "Moodie", "given": "Lindon W K", "initials": "LWK", "orcid": "0000-0002-9500-4535", "researcher": {"href": "https://publications.scilifelab.se/researcher/d9377be68ffc416690153f44ab45de21.json"}}, {"family": "Lundkvist", "given": "\u00c5ke", "initials": "\u00c5"}, {"family": "van Hemert", "given": "Martijn J", "initials": "MJ"}, {"family": "Neyts", "given": "Johan", "initials": "J"}, {"family": "Lennerstrand", "given": "Johan", "initials": "J"}, {"family": "Kihlberg", "given": "Jan", "initials": "J", "orcid": "0000-0002-4205-6040", "researcher": {"href": "https://publications.scilifelab.se/researcher/f9805d4f39cc48f79a6e6ba076917021.json"}}, {"family": "Sandberg", "given": "Kristian", "initials": "K", "orcid": "0000-0002-6395-6590", "researcher": {"href": "https://publications.scilifelab.se/researcher/2747d3fe7810406fafc429d9e66225ef.json"}}, {"family": "Danielson", "given": "U Helena", "initials": "UH", "orcid": "0000-0003-2728-0340", "researcher": {"href": "https://publications.scilifelab.se/researcher/b2bf7dffedf44237807c23718c72efa6.json"}}, {"family": "Carlsson", "given": "Jens", "initials": "J", "orcid": "0000-0003-4623-2977", "researcher": {"href": "https://publications.scilifelab.se/researcher/d7d91087358e46e38bb1b7110dc0b214.json"}}], "type": "journal article", "published": "2022-02-23", "journal": {"title": "J. Am. Chem. Soc.", "issn": "1520-5126", "issn-l": "0002-7863", "volume": "144", "issue": "7", "pages": "2905-2920"}, "abstract": "Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.", "doi": "10.1021/jacs.1c08402", "pmid": "35142215", "labels": {"Bioinformatics Support for Computational Resources": "Service", "Chemical Biology Consortium Sweden": "Service", "Drug Discovery and Development": "Collaborative"}, "xrefs": [{"db": "pmc", "key": "PMC8848513"}], "notes": [], "created": "2022-03-23T14:12:50.377Z", "modified": "2025-10-17T13:05:07.806Z"}]}