{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T07:04:41Z","timestamp":1792739081572,"version":"4.5.0"},"reference-count":40,"publisher":"American Chemical Society (ACS)","issue":"31","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006537","name":"Vanderbilt University","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100006537","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The increasing structural complexity of small-molecule therapeutics requires sensitive analytical techniques that facilitate rapid chiral analysis of drugs with multiple chiral centers. Here, we demonstrate ultrafast chiral separations for compounds possessing 3 chiral centers (8 stereoisomers, 4 enantiomer pairs) using gas-phase ion mobility spectrometry\u2013mass spectrometry (IM-MS). Separations are achieved using spontaneous noncovalent copper\u2013tyrosine complexation.This complexation strategy converts all stereoisomers into diastereomers that are structurally distinguishable by IM-MS. Notably, this strategy is over 3 orders of magnitude faster than traditional liquid-phase chiral chromatography (ms vs min, respectively). Using IM-MS, we achieved direct baseline separation of enantiomer pairs and progress toward differentiation of all 8 stereoisomers. Results suggest that higher-order complexes (i.e., copper\u2013tyrosine-bound drug dimers) enhance chiral differentiation at the expense of increased spectral complexity. Exchanging the chirality of the amino acid for complexation resulted in an inversion of separation elution ordering. Peak fitting analysis suggests that an IM resolving power of several thousand is necessary to resolve all stereoisomers for quantitative purposes, which is approximately an order of magnitude higher than the current state-of-the-art. Collectively, these findings demonstrate the speed and versatility of gas-phase ion mobility spectrometry for complex chiral analysis.<\/jats:p>","DOI":"10.1021\/acs.analchem.6c03422","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:18:40Z","timestamp":1785849520000},"page":"22627-22635","source":"Crossref","is-referenced-by-count":1,"title":["Rapid Chiral\nAnalysis of Drugs with Multiple Stereocenters\nvia High-Resolution Ion Mobility"],"prefix":"10.1021","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3263-5289","authenticated-orcid":true,"given":"Benjamin K.","family":"Blakley","sequence":"first","affiliation":[{"name":"Vanderbilt University , , , ,","place":["Nashville, Tennessee, United States, 37235-1822"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4871-5024","authenticated-orcid":true,"given":"Jody C.","family":"May","sequence":"additional","affiliation":[{"name":"Vanderbilt University , , , ,","place":["Nashville, Tennessee, United States, 37235-1822"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Guidolin","sequence":"additional","affiliation":[{"name":"Pfizer, Inc., Pharmaceutical Sciences Small Molecules (PSSM) , , ,","place":["Groton, Connecticut, United States, 06340"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bao","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Pfizer, Inc., Pharmaceutical Sciences Small Molecules (PSSM) , , ,","place":["Groton, Connecticut, United States, 06340"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8918-6419","authenticated-orcid":true,"given":"John A.","family":"McLean","sequence":"additional","affiliation":[{"name":"Vanderbilt University , , , ,","place":["Nashville, Tennessee, United States, 37235-1822"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"issue":"D1","key":"2026081109100545500_cit1","doi-asserted-by":"publisher","first-page":"D1307","DOI":"10.1093\/nar\/gkab918","article-title":"NCATS Inxight Drugs: A Comprehensive\nand Curated Portal for Translational Research","volume":"50","author":"Siramshetty","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"2026081109100545500_cit2","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.jhealeco.2016.01.012","article-title":"Innovation in the Pharmaceutical\nIndustry: New Estimates of R&D Costs","volume":"47","author":"DiMasi","year":"2016","journal-title":"J.\nHealth Econ."},{"issue":"6","key":"2026081109100545500_cit3","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.15445","article-title":"Costs of Drug Development\nand Research and Development Intensity in the US, 2000\u20132018","volume":"7","author":"Sertkaya","year":"2024","journal-title":"JAMA Netw. Open"},{"issue":"8","key":"2026081109100545500_cit4","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.1021\/ac001150v","article-title":"Mass Spectrometric\nQuantitation of\nChiral Drugs by the Kinetic Method","volume":"73","author":"Tao","year":"2001","journal-title":"Anal. Chem."},{"issue":"6683","key":"2026081109100545500_cit5","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1126\/science.adj8342","article-title":"Differentiating\nEnantiomers by Directional Rotation\nof Ions in a Mass Spectrometer","volume":"383","author":"Zhou","year":"2024","journal-title":"Science"},{"issue":"22","key":"2026081109100545500_cit6","doi-asserted-by":"publisher","first-page":"10887","DOI":"10.1021\/ac402580j","article-title":"13C NMR Spectroscopy for the Differentiation\nof Enantiomers Using Chiral Solvating Agents","volume":"85","author":"Pe\u0301rez-Trujillo","year":"2013","journal-title":"Anal. Chem."},{"key":"2026081109100545500_cit7","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/j.jpba.2018.04.033","article-title":"Enantiomeric Impurity\nAnalysis Using Circular Dichroism Spectroscopy with United States\nPharmacopeia Liquid Chromatographic Methods","volume":"156","author":"Kirkpatrick","year":"2018","journal-title":"J. Pharm. Biomed. Anal."},{"issue":"6","key":"2026081109100545500_cit8","doi-asserted-by":"publisher","first-page":"3545","DOI":"10.1021\/acs.analchem.6b04834","article-title":"Ultrafast Chiral\nChromatography as the Second Dimension in Two-Dimensional Liquid Chromatography\nExperiments","volume":"89","author":"Barhate","year":"2017","journal-title":"Anal. Chem."},{"issue":"3","key":"2026081109100545500_cit9","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1021\/ac504720m","article-title":"Ion Mobility-Mass\nSpectrometry: Time-Dispersive Instrumentation","volume":"87","author":"May","year":"2015","journal-title":"Anal. Chem."},{"issue":"11","key":"2026081109100545500_cit10","doi-asserted-by":"publisher","first-page":"2185","DOI":"10.1007\/s13361-019-02288-2","article-title":"Ion Mobility Spectrometry: Fundamental Concepts, Instrumentation,\nApplications, and the Road Ahead","volume":"30","author":"Dodds","year":"2019","journal-title":"J. Am. Soc.\nMass Spectrom."},{"key":"2026081109100545500_cit11","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1021\/jasms.2c00059","article-title":"Enantiomer\nDifferentiation of Amino\nAcid Stereoisomers by Structural Mass Spectrometry Using Noncovalent\nTrinuclear Copper Complexes","volume":"33","author":"Zlibut","year":"2022","journal-title":"J. Am. Soc. Mass\nSpectrom."},{"issue":"31","key":"2026081109100545500_cit12","doi-asserted-by":"publisher","first-page":"12892","DOI":"10.1021\/acs.analchem.4c02710","article-title":"Direct\nEnantiomer Differentiation of Drugs and Drug-Like Compounds via Noncovalent\nCopper\u2013Amino Acid Complexation and Ion Mobility-Mass Spectrometry","volume":"96","author":"Blakley","year":"2024","journal-title":"Anal. Chem."},{"key":"2026081109100545500_cit13","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.aca.2017.05.026","article-title":"Chiral Differentiation\nof Amino Acids through Binuclear\nCopper Bound Tetramers by Ion Mobility Mass Spectrometry","volume":"981","author":"Yu","year":"2017","journal-title":"Anal. Chim. Acta"},{"issue":"8","key":"2026081109100545500_cit14","doi-asserted-by":"publisher","first-page":"3234","DOI":"10.1039\/C4SC00443D","article-title":"Enantiomeric Differentiation\nof Aromatic\nAmino Acids Using Traveling Wave Ion Mobility-Mass Spectrometry","volume":"5","author":"Domalain","year":"2014","journal-title":"Chem. Sci."},{"issue":"11","key":"2026081109100545500_cit15","doi-asserted-by":"publisher","first-page":"4133","DOI":"10.1021\/ac702262k","article-title":"Terbutaline\nEnantiomer Separation and Quantification by Complexation and Field\nAsymmetric Ion Mobility Spectrometry-Tandem Mass Spectrometry","volume":"80","author":"Mie","year":"2008","journal-title":"Anal. Chem."},{"issue":"7","key":"2026081109100545500_cit16","doi-asserted-by":"publisher","first-page":"2850","DOI":"10.1021\/ac0618627","article-title":"Enantiomer Separation\nof Amino Acids by Complexation\nwith Chiral Reference Compounds and High-Field Asymmetric Waveform\nIon Mobility Spectrometry: Preliminary Results and Possible Limitations","volume":"79","author":"Mie","year":"2007","journal-title":"Anal. Chem."},{"issue":"4","key":"2026081109100545500_cit17","doi-asserted-by":"publisher","first-page":"2335","DOI":"10.1021\/acs.analchem.5b04280","article-title":"Multidimensional\nAnalysis of 16 Glucose Isomers by Ion Mobility Spectrometry","volume":"88","author":"Gaye","year":"2016","journal-title":"Anal. 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Mass Spectrom."},{"issue":"1","key":"2026081109100545500_cit20","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1007\/s13361-016-1523-9","article-title":"Structural Characterization of Monomers\nand Oligomers of D-Amino Acid-Containing Peptides Using T-Wave Ion\nMobility Mass Spectrometry","volume":"28","author":"Pang","year":"2017","journal-title":"J. Am. Soc. Mass\nSpectrom."},{"key":"2026081109100545500_cit21","doi-asserted-by":"publisher","first-page":"6903","DOI":"10.1007\/s00216-025-06178-3","article-title":"A Tunable Analytical\nPlatform for\nBile Acid Isomers: From Molecular Recognition to Pharmaceutical Quality\nControl","volume":"417","author":"Zhang","year":"2025","journal-title":"Anal. Bioanal. Chem."},{"key":"2026081109100545500_cit22","doi-asserted-by":"publisher","first-page":"2458","DOI":"10.1021\/jasms.4c00258","article-title":"Identifying\nand Quantifying Relative\nConcentrations of Epimers in Mixtures via Cyclic Ion Mobility Mass\nSpectrometry: Dexamethasone and Betamethasone as a Case Study","volume":"35","author":"Mane","year":"2024","journal-title":"J. Am. Soc. Mass Spectrom."},{"issue":"6","key":"2026081109100545500_cit23","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1021\/jasms.5c00054","article-title":"Distinguishing\nChiral Amino Acids Using Chiral Derivatization and Differential Ion\nMobility Mass Spectrometry","volume":"36","author":"Zhang","year":"2025","journal-title":"J. Am. Soc. Mass\nSpectrom."},{"issue":"73","key":"2026081109100545500_cit24","doi-asserted-by":"publisher","first-page":"10916","DOI":"10.1039\/D3CC01963B","article-title":"Charged Chiral Derivatization for Enantioselective\nImaging of D-,L-2-Hydroxyglutaric Acid Using Ion Mobility Spectrometry\/Mass\nSpectrometry","volume":"59","author":"Sugiyama","year":"2023","journal-title":"Chem. Commun."},{"key":"2026081109100545500_cit25","doi-asserted-by":"publisher","first-page":"3148","DOI":"10.1002\/elps.201800294","article-title":"Distinguishing Enantiomeric\nAmino Acids with Chiral Cyclodextrin Adducts and Structures for Lossless\nIon Manipulations","volume":"39","author":"Nagy","year":"2018","journal-title":"Electrophoresis"},{"key":"2026081109100545500_cit26","doi-asserted-by":"publisher","first-page":"20982","DOI":"10.1021\/acs.analchem.5c03830","article-title":"Molecular-Level\nInsights into TIMS-MS Separation of \u03b1\/\u03b2-Estradiol Isomers:\nSynergistic Effects of Cyclodextrins and Metal Ions","volume":"97","author":"Wu","year":"2025","journal-title":"Anal. Chem."},{"key":"2026081109100545500_cit27","doi-asserted-by":"publisher","DOI":"10.1016\/j.carbpol.2025.123260","article-title":"Elucidation\nof Molecular\nRecognition of Catecholamine Enantiomer by Cyclodextrin Combined Ion\nMobility Spectrometry and Theoretical Calculation","volume":"353","author":"Du","year":"2025","journal-title":"Carbohydr. Polym."},{"issue":"19","key":"2026081109100545500_cit28","doi-asserted-by":"publisher","first-page":"6792","DOI":"10.1021\/ac060439v","article-title":"Exploring Crown\nEthers as Shift Reagents\nfor Ion Mobility Spectrometry","volume":"78","author":"Hilderbrand","year":"2006","journal-title":"Anal. Chem."},{"key":"2026081109100545500_cit29","doi-asserted-by":"publisher","first-page":"6973","DOI":"10.1007\/s00216-025-06186-3","article-title":"Noncovalent Crown\nEther\u2013Assisted Separation of Stereoisomeric Glycosphingosines\nUsing Cyclic Ion Mobility Spectrometry","volume":"417","author":"Pang","year":"2025","journal-title":"Anal.\nBioanal. Chem."},{"key":"2026081109100545500_cit30","doi-asserted-by":"publisher","DOI":"10.1016\/j.aca.2025.344000","article-title":"Structure Elucidation and Discrimination of Peptides\nEpimers Induced by Chiral Residue by Ion Mobility Mass Spectrometry","volume":"1355","author":"Du","year":"2025","journal-title":"Anal. Chim. Acta"},{"issue":"13","key":"2026081109100545500_cit31","doi-asserted-by":"publisher","first-page":"5521","DOI":"10.1021\/acs.jmedchem.7b00231","article-title":"Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-Fluoro-5-Oxopyrrolidin-2-Yl]Methoxy}-7-Methoxyisoquinoline-6-Carboxamide\n(PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor\nAssociated Kinase 4 (IRAK4), by Fragment-Based Drug Design","volume":"60","author":"Lee","year":"2017","journal-title":"J. Med. Chem."},{"issue":"3","key":"2026081109100545500_cit32","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1021\/acs.jproteome.1c00425","article-title":"A Preprocessing\nTool for Enhanced Ion Mobility-Mass\nSpectrometry-Based Omics Workflows","volume":"21","author":"Bilbao","year":"2022","journal-title":"J. Proteome\nRes."},{"issue":"17","key":"2026081109100545500_cit33","doi-asserted-by":"publisher","first-page":"9048","DOI":"10.1021\/acs.analchem.7b01729","article-title":"An Interlaboratory\nEvaluation of Drift Tube Ion Mobility-Mass Spectrometry Collision\nCross Section Measurements","volume":"89","author":"Stow","year":"2017","journal-title":"Anal. Chem."},{"issue":"25","key":"2026081109100545500_cit34","doi-asserted-by":"publisher","first-page":"9018","DOI":"10.1021\/acs.analchem.2c01062","article-title":"Microanalysis of Brain Angiotensin Peptides Using Ultrasensitive\nCapillary Electrophoresis Trapped Ion Mobility Mass Spectrometry","volume":"94","author":"Delaney","year":"2022","journal-title":"Anal. Chem."},{"issue":"9","key":"2026081109100545500_cit35","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24098111","article-title":"Serum Vitamin\nD Metabolites by HPLC-MS\/MS Combined with Differential Ion Mobility\nSpectrometry: Aspects of Sample Preparation without Derivatization","volume":"24","author":"Usoltseva","year":"2023","journal-title":"Int. J. Mol. Sci."},{"issue":"13","key":"2026081109100545500_cit36","doi-asserted-by":"publisher","first-page":"1832","DOI":"10.1021\/acs.accounts.1c00796","article-title":"Analysis of Complex\nMixtures by Chemosensing NMR Using Para-Hydrogen-Induced Hyperpolarization","volume":"55","author":"Fraser","year":"2022","journal-title":"Acc. Chem. Res."},{"issue":"40","key":"2026081109100545500_cit37","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202308692","article-title":"Fragment Screening\nand Fast Micromolar Detection on a Benchtop NMR Spectrometer Boosted\nby Photoinduced Hyperpolarization","volume":"62","author":"Stadler","year":"2023","journal-title":"Angew. Chem.,\nInt. Ed."},{"issue":"13","key":"2026081109100545500_cit38","doi-asserted-by":"publisher","first-page":"8564","DOI":"10.1021\/acs.analchem.9b01838","article-title":"A Cyclic Ion Mobility-Mass Spectrometry\nSystem","volume":"91","author":"Giles","year":"2019","journal-title":"Anal. Chem."},{"issue":"1","key":"2026081109100545500_cit39","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1021\/acs.analchem.6b04171","article-title":"Investigation\nof the Complete Suite\nof the Leucine and Isoleucine Isomers: Toward Prediction of Ion Mobility\nSeparation Capabilities","volume":"89","author":"Dodds","year":"2017","journal-title":"Anal. Chem."},{"key":"2026081109100545500_cit40","doi-asserted-by":"publisher","first-page":"4628","DOI":"10.1021\/acs.analchem.7b00185","article-title":"Serpentine Ultralong\nPath with Extended Routing (SUPER) High Resolution Traveling Wave\nIon Mobility-MS Using Structures for Lossless Ion Manipulations","volume":"89","author":"Deng","year":"2017","journal-title":"Anal. Chem."}],"container-title":["Analytical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.analchem.6c03422","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/98\/31\/22627\/66333015\/acs.analchem.6c03422.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/98\/31\/22627\/66333015\/acs.analchem.6c03422.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T13:23:22Z","timestamp":1786454602000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/ancham\/article\/98\/31\/22627\/5236913\/Rapid-Chiral-Analysis-of-Drugs-with-Multiple"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":40,"journal-issue":{"issue":"31","published-online":{"date-parts":[[2026,7,29]]},"published-print":{"date-parts":[[2026,8,11]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.analchem.6c03422","relation":{},"ISSN":["0003-2700","1520-6882"],"issn-type":[{"value":"0003-2700","type":"print"},{"value":"1520-6882","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,29]]}}}