{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T13:23:42Z","timestamp":1761657822772,"version":"build-2065373602"},"reference-count":83,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2021MB107"],"award-info":[{"award-number":["ZR2021MB107"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32171249","22375028"],"award-info":[{"award-number":["32171249","22375028"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The kappa opioid receptor (KOR) is one of class A G\u2010protein\u2010coupled receptors (GPCRs), playing important roles in pain sensation. The unique analgesic activity of KOR requires KOR activation that recruits downstream effectors. It is noted that KOR primarily couples to the G\n                    <jats:sub>i\/o<\/jats:sub>\n                    family proteins in the process of KOR signaling that contain the conventional (G\n                    <jats:sub>i1<\/jats:sub>\n                    , G\n                    <jats:sub>i2<\/jats:sub>\n                    , G\n                    <jats:sub>i3<\/jats:sub>\n                    , G\n                    <jats:sub>oA<\/jats:sub>\n                    , and G\n                    <jats:sub>oB<\/jats:sub>\n                    ) and nonconventional (G\n                    <jats:sub>z<\/jats:sub>\n                    and G\n                    <jats:sub>g<\/jats:sub>\n                    ) subtypes. The molecular mechanisms governing KOR signaling\u2014particularly its selectivity for G\n                    <jats:sub>i\/o<\/jats:sub>\n                    protein subtypes and the pathway specificity of its ligands\u2014remain unclear. Furthermore, the structural and energetic sequence of events during the activation of KOR and its cognate G\n                    <jats:sub>i\/o<\/jats:sub>\n                    proteins is poorly understood. This lack of knowledge hinders the structure\u2010based design of pharmacophores targeting the KOR\/G\n                    <jats:sub>i\/o<\/jats:sub>\n                    complex. It suggests that further research and investigation are required to analyze the crystal structure of the agonists\/KOR complexes and various intermediate states in the KOR activation pathway. Some improved enhanced sampling methods, such as umbrella sampling, metadynamics, and Markov State Model methods, can characterize the interaction between GPCRs and different G protein subtypes after specific ligands binding, and the free energy landscapes along the ligand binding pathway. In this review, we discuss the research advances in the molecular mechanisms of KOR signaling. We also present a brief overview of computational conformational sampling methods based on molecular dynamics, including the activation mechanisms, allosteric effects, and actions of biased ligands of GPCRs to describe their activation energy landscape. It can provide an insight into evaluate the convergence of free energy surfaces along coordinates of functional interest, which is helpful to understand the role of GPCR conformational ensembles in intracellular signal transduction.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70181","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T06:02:31Z","timestamp":1760508151000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Advances in the Molecular Mechanism of Kappa Opioid Receptors Signaling and the Important Sampling Methods to Probe the Activation Landscape of\n                    <scp>GPCRs<\/scp>"],"prefix":"10.1111","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7052-1018","authenticated-orcid":false,"given":"Mingqiong","family":"Tong","sequence":"first","affiliation":[{"name":"Shandong Engineering Research Center of Novel Pharmaceutical Excipients, Sustained and Controlled Release Preparations, College of Health and Medicine Dezhou University  Dezhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wan","family":"Sun","sequence":"additional","affiliation":[{"name":"Shandong Engineering Research Center of Novel Pharmaceutical Excipients, Sustained and Controlled Release Preparations, College of Health and Medicine Dezhou University  Dezhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pingxuan","family":"Dong","sequence":"additional","affiliation":[{"name":"Shandong Engineering Research Center of Novel Pharmaceutical Excipients, Sustained and Controlled Release Preparations, College of Health and Medicine Dezhou University  Dezhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinghe","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Engineering Research Center of Novel Pharmaceutical Excipients, Sustained and Controlled Release Preparations, College of Health and Medicine Dezhou University  Dezhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangling","family":"Gu","sequence":"additional","affiliation":[{"name":"Shandong Engineering Research Center of Novel Pharmaceutical Excipients, Sustained and Controlled Release Preparations, College of Health and Medicine Dezhou University  Dezhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zanxia","family":"Cao","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Biophysics, Institute of Biophysics Dezhou University  Dezhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0OB02175J"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.9b00150"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201700486R"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.24349"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.030304"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1103\/PhysRevLett.100.020603"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201044528\u2010w"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.3216567"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2009.05.008"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aav0320"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010biochem\u2010061620\u2010044044"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.10.029"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2014.04.002"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0500334102"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.07.033"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440\u20101681.1999.03049.x"},{"volume-title":"Protein Conformational Dynamics","year":"2014","author":"Da L. T.","key":"e_1_2_8_18_1"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201037041\u20107"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c01183"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22070"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb1134"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201006030\u20107"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204190"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.6b01238"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.04.044"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896\u20106273(00)80636\u20104"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.66"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.3701766"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003\u2010025\u201007630\u2010x"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.540130812"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1088\/0034\u20104885\/71\/12\/126601"},{"volume-title":"The Kappa Opioid Receptor","year":"2022","author":"Lazenka M. F.","key":"e_1_2_8_33_1"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2022.964724"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.3c00747"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.644644"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1303186110"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201025020\u20109"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1910006117"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1017\/qrd.2021.7"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2110085119"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19112"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.17424"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.12.020"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010017\u201002388\u20101"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12915\u2010017\u20100479\u2010y"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504778102"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.3c00526"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010020\u20100535\u20108"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.24533"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.3016896"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.3565032"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi100686t"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.642"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010022\u201001208\u2010y"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2012.06.012"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596\u2010020\u20100342\u20104"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2023.106966"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08144"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.182234399"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5500.2323"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.3c01130"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1099715"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28010346"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.3c00401"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.2978177"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar5002999"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b01233"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2013.76"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5500.2319"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/0021\u20109991(77)90121\u20108"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010024\u201001812\u20100"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.515668"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M609264200"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.2c00370"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201031652\u20102"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.1343"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2020.10.005"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.12.026"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.5011399"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201032213\u20103"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2016.01.013"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1038\/386499a0"},{"key":"e_1_2_8_84_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct200100e"}],"container-title":["Chemical Biology &amp; Drug Design"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cbdd.70181","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T13:19:07Z","timestamp":1761657547000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cbdd.70181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":83,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1111\/cbdd.70181"],"URL":"https:\/\/doi.org\/10.1111\/cbdd.70181","archive":["Portico"],"relation":{},"ISSN":["1747-0277","1747-0285"],"issn-type":[{"type":"print","value":"1747-0277"},{"type":"electronic","value":"1747-0285"}],"subject":[],"published":{"date-parts":[[2025,10]]},"assertion":[{"value":"2024-12-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70181"}}