[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-455646-105":59,"doc-detail-455646-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","ultra-large-virtual-screening-unveils-potent-agonists-of-the-neuromodulatory-orphan-receptor-gpr139-research-findings-on-gpcr-ligand-discovery","Ultra-large virtual screening unveils potent agonists of the neuromodulatory orphan receptor GPR139 - Research findings on GPCR ligand discovery","","Ultra-large virtual screening and experimental validation uncover potent agonists of the neuromodulatory orphan GPCR GPR139. A high-resolution receptor structure enables docking of 235 million compounds to the GPR139 binding site, yielding 68 top-ranked candidates, five of which are full agonists with potencies spanning 160 nM to 3.6 µM. Structure-guided optimization plus cryo-EM confirm predicted binding modes and support functional insights, including a mouse behavioral effect. The study also evaluates AlphaFold3 as a substitute for experimental structures, showing limited capability for receptor–ligand modeling for understudied GPCRs, while highlighting acceleration of drug discovery through structure plus large-library docking.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/ultra-large-virtual-screening-unveils-potent-agonists-of-the-neuromodulatory-orphan-receptor-gpr139-research-findings-on-gpcr-ligand-discovery/455646/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/ultra-large-virtual-screening-unveils-potent-agonists-of-the-neuromodulatory-orphan-receptor-gpr139-research-findings-on-gpcr-ligand-discovery/455646.png","ImageObject",300,407,{"name":92,"@type":93},"Levi","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-06","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How was GPR139 targeted to discover new ligands?","Question",{"text":112,"@type":113},"The study used structure-based virtual docking of 235 million compounds to the GPR139 binding site, followed by experimental evaluation of top-ranked candidates.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What experimental potency range was observed for the identified full agonists?",{"text":117,"@type":113},"Five experimentally tested full agonists showed potencies ranging from 160 nM to 3.6 µM.",{"name":119,"@type":110,"acceptedAnswer":120},"How did the researchers confirm the predicted binding mode?",{"text":121,"@type":113},"They performed structure-guided optimization and obtained a cryo-EM structure of the receptor–ligand complex to confirm the predicted binding mode.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},455646,1790878681,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":19,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":36},7971461740909,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Article [https://doi.org/10.1038/s41467-025-66845-y](https://doi.org/10.1038/s41467-025-66845-y)  \nUltra-large virtual screening unveils potent agonists ofthe neuromodulatory orphan receptor GPR139  \nReceived: 29 April 2025  \n\n| Accepted: 14 November 2025 |\n| --- |\n| |\n| Check for updates |\n\nIsrael Cabeza de Vaca 1,11, Boris Trapkov 2,11, Ling Shen3,11, Duy Duc Vo1, Xiaoqun Zhang 4, Yunting Yang4, Mitra Pezeshki 2, Xuehan Zhang3,5, Frida Bällgren6, Aljona Saleh6, Andrii V. Tarnovskiy7, Dmytro S. Radchenko 7  \n,  \nYurii S. Moroz 7,8,9, Hans Bräuner-Osborne2, Per Svenningsson 4, Jan Kihlberg 10, Zhi-Jie Liu 3,5 , Alexander Sebastian Hauser 2  & Jens Carlsson 1   \nThe 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 µM. 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 receptorligand interactions for understudied GPCRs. The results demonstrate how high-resolution GPCR structures combined with large-library docking can accelerate drug discovery.  \nIdentification of small-molecule ligands of proteins enables drug discovery and remains a cornerstone for development of therapeutic treatments. G protein-coupled receptors (GPCRs) have garnered significant attention due to their pivotal roles in physiological processes. Despite that GPCRs constitute only 15% of the druggable genes in the human genome, this large protein family is the target for more than  \n34% of approved drugs1. Breakthroughs in crystallography and cryoEM have enabled structure determination fora large number ofGPCRs, revealing the molecular basis of ligand binding to drug targets2. Furthermore, the recent development of accurate machine learning methods for protein structure prediction has the potential to further increase the structural coverage in the GPCR family3–5. Structure-based  \n1Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden. 2Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. 3iHuman Institute, ShanghaiTech University, Shanghai, China. 4Neuro Svenningsson, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden. 5School of Life Science and Technology, ShanghaiTech University, Shanghai, China. 6Department of Pharmacy, SciLifeLab Drug Discovery and Development, Uppsala University, Uppsala, Sweden. 7Enamine Ltd., Kyiv, Ukraine. 8Taras Shevchenko National University of Kyiv, Kyiv, Ukraine. 9Chemspace LLC, Kyiv, Ukraine. 10Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden. 11These authors contributed equally: Israel Cabeza de Vaca, Boris Trapkov, Ling Shen. e-mail: [liuzhj@shanghaitech.edu.cn](liuzhj@shanghaitech.edu.cn); [alexander.hauser@sund.ku.dk](alexander.hauser@sund.ku.dk);  \n[jens.carlsson@icm.uu.se](jens.carlsson@icm.uu.se)  \ndesign has proven to be an efficient strategy for discovering GPCR ligands and can now be applied to accelerate drug discovery for a large number of therapeutic targets6,7.  \nDespite the major interest in the physiological roles of GPCRs, the endogenous ligand and function of many members within this family remain unknown. In fact, more than 100 non-olf","cbCaijX0VFAub63i","https://ap.wps.com/l/cbCaijX0VFAub63i","pdf",3650596,16,"English","# Introduction\n## GPCRs, orphan receptors, and drug discovery\n## Need for chemical probes for orphan GPCRs\n# Results\n## Docking and experimental identification of GPR139 agonists\n## Structure-guided optimization and cryo-EM validation\n## Functional characterization and in vivo behavioral effects\n## Evaluating AlphaFold3 for receptor–ligand modeling","[{\"question\":\"How was GPR139 targeted to discover new ligands?\",\"answer\":\"The study used structure-based virtual docking of 235 million compounds to the GPR139 binding site, followed by experimental evaluation of top-ranked candidates.\"},{\"question\":\"What experimental potency range was observed for the identified full agonists?\",\"answer\":\"Five experimentally tested full agonists showed potencies ranging from 160 nM to 3.6 µM.\"},{\"question\":\"How did the researchers confirm the predicted binding mode?\",\"answer\":\"They performed structure-guided optimization and obtained a cryo-EM structure of the receptor–ligand complex to confirm the predicted binding mode.\"}]","Ultra-large virtual screening unveils potent agonists of the neuromodulatory orphan receptor GPR139 - Research findings on GPCR ligand discovery | PDF",1790743744]