{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:32:01Z","timestamp":1787045521191,"version":"3.56.0"},"reference-count":37,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T00:00:00Z","timestamp":1679961600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T00:00:00Z","timestamp":1679961600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T00:00:00Z","timestamp":1679961600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100009210","name":"Food and Drug Administration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009210","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM098818"],"award-info":[{"award-number":["R01GM098818"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The nation\u2019s opioid overdose deaths reached an all-time high in 2021. The majority of deaths are due to synthetic opioids represented by fentanyl. Naloxone, which is a FDA-approved reversal agent, antagonizes opioids through competitive binding at the \u03bc-opioid receptor (mOR). Thus, knowledge of the opioid\u2019s residence time is important for assessing the effectiveness of naloxone. Here, we estimated the residence times (\u03c4) of 15 fentanyl and 4 morphine analogs using metadynamics and compared them with the most recent measurement of the opioid kinetic, dissociation, and naloxone inhibitory constants (Mann et al. Clin. Pharmacol. Therapeut.\u00a02022, 120, 1020\u20131232). Importantly, the microscopic simulations offered a glimpse at the common binding mechanism and molecular determinants of dissociation kinetics for fentanyl analogs. The insights inspired us to develop a machine learning approach to analyze the kinetic impact of fentanyl\u2019s substituents based on the interactions with mOR residues. This proof-of-concept approach is general; for example, it may be used to tune ligand residence times in computer-aided drug discovery.<\/jats:p>","DOI":"10.1021\/acs.jcim.3c00069","type":"journal-article","created":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T15:38:16Z","timestamp":1680017896000},"page":"2196-2206","source":"Crossref","is-referenced-by-count":19,"title":["Structure\u2013Kinetics Relationships of Opioids\nfrom Metadynamics and Machine Learning Analysis"],"prefix":"10.1021","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2216-4482","authenticated-orcid":true,"given":"Paween","family":"Mahinthichaichan","sequence":"first","affiliation":[{"name":"United States Food and Drug Administration , , , ,","place":["Silver Spring, Maryland, United States, 20993"]},{"name":"University of Maryland School of Pharmacy , , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8395-9353","authenticated-orcid":true,"given":"Ruibin","family":"Liu","sequence":"additional","affiliation":[{"name":"University of Maryland School of Pharmacy , , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3789-4880","authenticated-orcid":true,"given":"Quynh N.","family":"Vo","sequence":"additional","affiliation":[{"name":"United States Food and Drug Administration , , , ,","place":["Silver Spring, Maryland, United States, 20993"]},{"name":"University of Maryland School of Pharmacy , , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3150-2981","authenticated-orcid":true,"given":"Christopher R.","family":"Ellis","sequence":"additional","affiliation":[{"name":"United States Army , , , ,","place":["Aberdeen\nProving Ground, Maryland, United States, 21010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6307-2314","authenticated-orcid":true,"given":"Lidiya","family":"Stavitskaya","sequence":"additional","affiliation":[{"name":"United States Food and Drug Administration , , , ,","place":["Silver Spring, Maryland, United States, 20993"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3234-0769","authenticated-orcid":true,"given":"Jana","family":"Shen","sequence":"additional","affiliation":[{"name":"University of Maryland School of Pharmacy , , , ,","place":["Baltimore, Maryland, United States, 21201"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2023,3,28]]},"reference":[{"key":"2026081804444917600_cit1","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.1152\/jn.00017.2021","article-title":"Neuronal Mechanisms Underlying Opioid-Induced Respiratory\nDepression: Our Current Understanding","volume":"125","author":"Ramirez","year":"2021","journal-title":"J. Neurophysiol"},{"key":"2026081804444917600_cit2","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/j.tips.2018.02.004","article-title":"Chemical Diversity\nin the G Protein-Coupled Receptor\nSuperfamily","volume":"39","author":"Vass","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"2026081804444917600_cit3","doi-asserted-by":"publisher","first-page":"2428","DOI":"10.1021\/acschemneuro.8b00174","article-title":"DARK Classics in Chemical Neuroscience:\nFentanyl","volume":"9","author":"Burns","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"2026081804444917600_cit4","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.neubiorev.2018.12.005","article-title":"Fentanyl: Receptor\nPharmacology, Abuse Potential, and\nImplications for Treatment","volume":"106","author":"Comer","year":"2019","journal-title":"Neurosci. Biobehav.\nRev."},{"key":"2026081804444917600_cit5","doi-asserted-by":"publisher","first-page":"385","DOI":"10.4155\/fmc.13.215","article-title":"Fentanyl-Related Compounds and Derivatives: Current\nStatus and Future Prospects for Pharmaceutical Applications","volume":"6","author":"Vardanyan","year":"2014","journal-title":"Future medicinal chemistry"},{"key":"2026081804444917600_cit6","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.neuropharm.2017.10.016","article-title":"Fentanyl, Fentanyl\nAnalogs and Novel Synthetic Opioids: A Comprehensive Review","volume":"134","author":"Armenian","year":"2018","journal-title":"Neuropharmacol"},{"key":"2026081804444917600_cit7","doi-asserted-by":"publisher","first-page":"3955","DOI":"10.1021\/acschemneuro.0c00441","article-title":"DARK Classics in\nChemical Neuroscience: Carfentanil","volume":"11","author":"Ringuette","year":"2020","journal-title":"ACS Chem.\nNeurosci."},{"key":"2026081804444917600_cit8","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1007\/s11419-017-0379-4","article-title":"Fentanyls continue to replace heroin in the drug arena:\nthe cases of ocfentanil and carfentanil","volume":"36","author":"Misailidi","year":"2018","journal-title":"Forensic\nToxicol"},{"key":"2026081804444917600_cit9","doi-asserted-by":"publisher","first-page":"108019","DOI":"10.1016\/j.pharmthera.2021.108019","article-title":"Treatment\nof overdose in the synthetic opioid era","volume":"233","author":"Skolnick","year":"2022","journal-title":"Pharmacol.\nThera"},{"key":"2026081804444917600_cit10","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s13011-019-0195-4","article-title":"Higher Doses of\nNaloxone Are Needed in the Synthetic\nOpioid Era","volume":"14","author":"Moss","year":"2019","journal-title":"Subst. Abuse Treat. Prev. Policy"},{"key":"2026081804444917600_cit11","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1002\/cpt.2696","article-title":"Development of a Translational\nModel to Assess the Impact of Opioid\nOverdose and Naloxone Dosing on Respiratory Depression and Cardiac\nArrest","volume":"112","author":"Mann","year":"2022","journal-title":"Clin. Pharmacol. Therapeut."},{"key":"2026081804444917600_cit12","doi-asserted-by":"publisher","first-page":"2208","DOI":"10.1021\/jacsau.1c00341","article-title":"Kinetics and Mechanism\nof Fentanyl Dissociation from the \u03bc-Opioid Receptor","volume":"1","author":"Mahinthichaichan","year":"2021","journal-title":"JACS Au"},{"key":"2026081804444917600_cit13","doi-asserted-by":"publisher","first-page":"12562","DOI":"10.1073\/pnas.202427399","article-title":"Escaping Free-Energy Minima","volume":"99","author":"Laio","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081804444917600_cit14","doi-asserted-by":"publisher","first-page":"020603","DOI":"10.1103\/PhysRevLett.100.020603","article-title":"Well-Tempered\nMetadynamics: A Smoothly\nConverging and Tunable Free-Energy Method","volume":"100","author":"Barducci","year":"2008","journal-title":"Phys.\nRev. Lett."},{"key":"2026081804444917600_cit15","doi-asserted-by":"publisher","first-page":"E386","DOI":"10.1073\/pnas.1424461112","article-title":"Kinetics of\nProtein\u2013Ligand Unbinding: Predicting Pathways, Rates, and Rate-Limiting\nSteps","volume":"112","author":"Tiwary","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026081804444917600_cit16","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/nature14886","article-title":"Structural Insights\ninto \u03bc-Opioid Receptor Activation","volume":"524","author":"Huang","year":"2015","journal-title":"Nature"},{"key":"2026081804444917600_cit17","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1038\/s41467-021-21262-9","article-title":"How \u03bc-Opioid\nReceptor Recognizes Fentanyl","volume":"12","author":"Vo","year":"2021","journal-title":"Nat. Commun."},{"key":"2026081804444917600_cit18","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1021\/ct5010615","article-title":"WESTPA: An Interoperable,\nHighly Scalable Software Package for Weighted Ensemble Simulation\nand Analysis","volume":"11","author":"Zwier","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"2026081804444917600_cit19","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/S1043-9471(05)80049-7","article-title":"Integrated\nMethods for the Construction of Three Dimensional Models and Computational\nProbing of Structure-Function Relations in G-Protein Coupled Receptors","volume-title":"Receptor Molecular Biology, Methods in Neurosciences","author":"Ballesteros","year":"1995"},{"key":"2026081804444917600_cit20","doi-asserted-by":"publisher","first-page":"4780","DOI":"10.1021\/jacs.6b12950","article-title":"Unbinding\nKinetics of a P38 MAP Kinase Type II Inhibitor from Metadynamics Simulations","volume":"139","author":"Casasnovas","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"2026081804444917600_cit21","doi-asserted-by":"publisher","first-page":"124105","DOI":"10.1063\/5.0019100","article-title":"A Combination of Machine\nLearning and Infrequent Metadynamics to Efficiently Predict Kinetic\nRates, Transition States, and Molecular Determinants of Drug Dissociation\nfrom G Protein-Coupled Receptors","volume":"153","author":"Lamim\nRibeiro","year":"2020","journal-title":"J. Chem. Phys."},{"key":"2026081804444917600_cit22","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1021\/acs.jcim.6b00679","article-title":"Metadynamics\nSimulations Distinguish\nShort- and Long-Residence-Time Inhibitors of Cyclin-Dependent Kinase\n8","volume":"57","author":"Callegari","year":"2017","journal-title":"J. Chem. Inf. Model."},{"key":"2026081804444917600_cit23","doi-asserted-by":"publisher","first-page":"230602","DOI":"10.1103\/PhysRevLett.111.230602","article-title":"From Metadynamics\nto Dynamics","volume":"111","author":"Tiwary","year":"2013","journal-title":"Phys. Rev. Lett."},{"key":"2026081804444917600_cit24","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/nature10954","article-title":"Crystal Structure of\nthe M-Opioid\nReceptor Bound to a Morphinan Antagonist","volume":"485","author":"Manglik","year":"2012","journal-title":"Nature"},{"key":"2026081804444917600_cit25","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1021\/ct500040r","article-title":"Assessing\nthe Reliability of the\nDynamics Reconstructed from Metadynamics","volume":"10","author":"Salvalaglio","year":"2014","journal-title":"J.\nChem. Theory Comput."},{"key":"2026081804444917600_cit26","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.1002\/jcc.21305","article-title":"Reconstructing the Equilibrium Boltzmann\nDistribution from Well-Tempered Metadynamics","volume":"30","author":"Bonomi","year":"2009","journal-title":"J. Comput. Chem."},{"key":"2026081804444917600_cit27","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1016\/j.cpc.2013.09.018","article-title":"PLUMED 2: New Feathers for an Old Bird","volume":"185","author":"Tribello","year":"2014","journal-title":"Comput.\nPhys. Commun."},{"key":"2026081804444917600_cit28","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.ejphar.2005.08.008","article-title":"[3H]\u00adAlvimopan Binding\nto the \u03bc\nOpioid Receptor: Comparative Binding Kinetics of Opioid Antagonists","volume":"520","author":"Cassel","year":"2005","journal-title":"Eur. J. Pharmacol."},{"key":"2026081804444917600_cit29","doi-asserted-by":"publisher","first-page":"107718","DOI":"10.1016\/j.neuropharm.2019.107718","article-title":"Biased Agonism\nof Clinically Approved \u03bc-Opioid Receptor Agonists and TRV130\nIs Not Controlled by Binding and Signaling Kinetics","volume":"166","author":"Pedersen","year":"2020","journal-title":"Neuropharmacol"},{"key":"2026081804444917600_cit30","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/s41586-018-0219-7","article-title":"Structure of the \u03bc-Opioid Receptor-Gi Protein Complex","volume":"558","author":"Koehl","year":"2018","journal-title":"Nature"},{"key":"2026081804444917600_cit31","volume-title":"PyCaret: An open source,\nlow-code machine learning library in Python","author":"Ali","year":"2020"},{"key":"2026081804444917600_cit32","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random Forests","volume":"45","author":"Breiman","year":"2001","journal-title":"Mach. Learn."},{"key":"2026081804444917600_cit33","unstructured":"Lundberg, S. M.; Lee, S.-I.\n          A Unified Approach\nto Interpreting Model Predictions. In NIPS'17:\nProceedings of the 31st International Conference on Neural Information\nProcessing Systems, 2017."},{"key":"2026081804444917600_cit34","doi-asserted-by":"publisher","first-page":"4361","DOI":"10.1016\/j.cell.2022.09.041","article-title":"Molecular Recognition of Morphine and Fentanyl by the Human \u03bc-Opioid\nReceptor","volume":"185","author":"Zhuang","year":"2022","journal-title":"Cell"},{"key":"2026081804444917600_cit35","doi-asserted-by":"publisher","first-page":"6373","DOI":"10.1021\/acs.jpclett.0c00999","article-title":"Accuracy of Molecular Simulation-Based\nPredictions of koff Values: A Metadynamics\nStudy","volume":"11","author":"Capelli","year":"2020","journal-title":"J. Phys. Chem. Lett."},{"key":"2026081804444917600_cit36","doi-asserted-by":"publisher","first-page":"2309","DOI":"10.1016\/j.csbj.2022.05.013","article-title":"A Comprehensive\nEvaluation of the\nPotential Binding Poses of Fentanyl and Its Analogs at the M-Opioid Receptor","volume":"20","author":"Xie","year":"2022","journal-title":"Comput. Struct.\nBiotechnol. J."},{"key":"2026081804444917600_cit37","doi-asserted-by":"publisher","first-page":"na","DOI":"10.1038\/s41589-022-01208-y","article-title":"Insights into\nDistinct Signaling Profiles of the \u03bcOR Activated by Diverse\nAgonists","author":"Qu","year":"2022","journal-title":"Nat. Chem. Biol."}],"container-title":["Journal of Chemical Information and Modeling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jcim.3c00069","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/63\/7\/2196\/8909624\/ci3c00069.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/63\/7\/2196\/8909624\/ci3c00069.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:01:14Z","timestamp":1787043674000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article\/63\/7\/2196\/850349\/Structure-Kinetics-Relationships-of-Opioids-from"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,28]]},"references-count":37,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,3,28]]},"published-print":{"date-parts":[[2023,4,10]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jcim.3c00069","relation":{},"ISSN":["1549-9596","1549-960X"],"issn-type":[{"value":"1549-9596","type":"print"},{"value":"1549-960X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,28]]}}}