{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T19:08:38Z","timestamp":1780081718632,"version":"3.54.0"},"reference-count":45,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T00:00:00Z","timestamp":1756166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS)","award":["202321990"],"award-info":[{"award-number":["202321990"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["JP23245005"],"award-info":[{"award-number":["JP23245005"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["JP16KT0059"],"award-info":[{"award-number":["JP16KT0059"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["JP25810103"],"award-info":[{"award-number":["JP25810103"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["JP15KT0146"],"award-info":[{"award-number":["JP15KT0146"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["JP16K08321"],"award-info":[{"award-number":["JP16K08321"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["JP20H00588"],"award-info":[{"award-number":["JP20H00588"]}]},{"name":"Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)","award":["202321990"],"award-info":[{"award-number":["202321990"]}]},{"name":"Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)","award":["JP23245005"],"award-info":[{"award-number":["JP23245005"]}]},{"name":"Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)","award":["JP16KT0059"],"award-info":[{"award-number":["JP16KT0059"]}]},{"name":"Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)","award":["JP25810103"],"award-info":[{"award-number":["JP25810103"]}]},{"name":"Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)","award":["JP15KT0146"],"award-info":[{"award-number":["JP15KT0146"]}]},{"name":"Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)","award":["JP16K08321"],"award-info":[{"award-number":["JP16K08321"]}]},{"name":"Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)","award":["JP20H00588"],"award-info":[{"award-number":["JP20H00588"]}]},{"name":"Japan Science and Technology Agency (JST), CREST","award":["202321990"],"award-info":[{"award-number":["202321990"]}]},{"name":"Japan Science and Technology Agency (JST), CREST","award":["JP23245005"],"award-info":[{"award-number":["JP23245005"]}]},{"name":"Japan Science and Technology Agency (JST), CREST","award":["JP16KT0059"],"award-info":[{"award-number":["JP16KT0059"]}]},{"name":"Japan Science and Technology Agency (JST), CREST","award":["JP25810103"],"award-info":[{"award-number":["JP25810103"]}]},{"name":"Japan Science and Technology Agency (JST), CREST","award":["JP15KT0146"],"award-info":[{"award-number":["JP15KT0146"]}]},{"name":"Japan Science and Technology Agency (JST), CREST","award":["JP16K08321"],"award-info":[{"award-number":["JP16K08321"]}]},{"name":"Japan Science and Technology Agency (JST), CREST","award":["JP20H00588"],"award-info":[{"award-number":["JP20H00588"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The mechanism of separating the small chiral drug molecules on large soft polymers is essential in pharmaceutical science. As a case study, the differentiation mechanism of ibuprofen, (R,S)-2-(4-isobutylphenyl)propanoic acid, with cellulose tris(4-methylbenzoate) (CMB) as the chiral stationary phase (CSP) was investigated by combining the molecular docking simulation and multi-level layered terminal-to-center elongation (ML-T2C-ELG) method. Our results demonstrated that, based on the optimized geometry using the ML-T2C-ELG method, the complexation energy of S-ibuprofen with CMB obtained at B3LYP-D3(BJ)\/6-311G(d) level is more negative than that of R-ibuprofen, which is caused by the greater hydrogen bonding and \u03c0-\u03c0 stacking interactions between CMB and S-ibuprofen. The results are in line with the experimental observations of high-performance liquid chromatography (HPLC) that the retention time of S-ibuprofen on CMB is longer than that of R-ibuprofen. Moreover, the ML-T2C-ELG method was found to be valuable for optimizing the geometries of such flexible and large systems, which allows for a more accurate description of interactions between soft polymers and small molecules when coupled with the docking simulation. It is anticipated that this study can provide beneficial insights for future optical resolution mechanisms of other chiral drugs.<\/jats:p>","DOI":"10.3390\/molecules30173503","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T14:18:49Z","timestamp":1756217929000},"page":"3503","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Theoretical Examination on the Chiral Separation Mechanism of Ibuprofen on Cellulose Tris(4-methylbenzoate)"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-323X","authenticated-orcid":false,"given":"Xiao","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Material Sciences, Faculty of Engineering Sciences, Kyushu University, 6-1 Kasuga Park, Fukuoka 816-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8457-2425","authenticated-orcid":false,"given":"Yuuichi","family":"Orimoto","sequence":"additional","affiliation":[{"name":"Department of Material Sciences, Faculty of Engineering Sciences, Kyushu University, 6-1 Kasuga Park, Fukuoka 816-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5243-8192","authenticated-orcid":false,"given":"Yuriko","family":"Aoki","sequence":"additional","affiliation":[{"name":"Department of Material Sciences, Faculty of Engineering Sciences, Kyushu University, 6-1 Kasuga Park, Fukuoka 816-8580, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e23647","DOI":"10.1002\/chir.23647","article-title":"Enantioselective Separation and Determination of Ibuprofen: Stereoselective Pharmacokinetics, Pharmacodynamics and Analytical Methods","volume":"36","author":"Vashistha","year":"2024","journal-title":"Chirality"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.2165\/00003088-199834020-00002","article-title":"Clinical Pharmacokinetics of Ibuprofen. The first 30 years","volume":"34","author":"Davies","year":"1998","journal-title":"Clin. Pharmacokinet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/BF03342662","article-title":"Comparative Pharmacology of S(+)-ibuprofen and (RS)-ibuprofen","volume":"20","author":"Evans","year":"2001","journal-title":"Clin. Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1023\/A:1018969506143","article-title":"Pharmacokinetics and Bioinversion of Ibuprofen Enantiomers in Humans","volume":"11","author":"Cheng","year":"1994","journal-title":"Pharm. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/BF02336690","article-title":"Pharmacokinetics of S(+)- and R(\u2212)-ibuprofen in Volunteers and First Clinical Experience of S(+)-ibuprofen in Rheumatoid Arthritis","volume":"38","author":"Geisslinger","year":"1990","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"760","DOI":"10.2174\/156802611795165098","article-title":"The Significance of Chirality in Drug Design and Development","volume":"11","author":"Brooks","year":"2011","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2566","DOI":"10.1002\/elps.201800220","article-title":"Enantiomeric Quality Control of R-Tofisopam by HPLC using Polysaccharide-Type Chiral Stationary Phases in Polar Organic Mode","volume":"39","author":"Foroughbakhshfasaei","year":"2018","journal-title":"Electrophoresis"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.jpba.2017.07.008","article-title":"The Market of Chiral Drugs: Chiral Switches versus de novo Enantiomerically Pure Compounds","volume":"147","author":"Calcaterra","year":"2018","journal-title":"J. Pharmaceut. Biomed. Anal."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1002\/chir.22715","article-title":"Enantioselective Analysis of Ibuprofen Enantiomers in Mice Plasma and Tissues by High-Performance Liquid Chromatography with Fluorescence Detection: Application to a Pharmacokinetic Study","volume":"29","author":"Cios","year":"2017","journal-title":"Chirality"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"463095","DOI":"10.1016\/j.chroma.2022.463095","article-title":"Experimental and Computational Studies of Enantioseparation of Three Profen Enantiomers with a Focus on Quantification of the Enantiomeric Impurities Present in the Corresponding Enantiopure S-profen Drugs","volume":"1673","author":"Cao","year":"2022","journal-title":"J. Chromatogr. A"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1002\/elps.202200205","article-title":"Enantioseparation of Planar Chiral Ferrocenes on Cellulose-Based Chiral Stationary Phases: Benzoate versus Carbamate Pendant Groups","volume":"44","author":"Dallocchio","year":"2023","journal-title":"Electrophoresis"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Dallocchio, R., Dess\u00ec, A., Sechi, B., and Peluso, P. (2023). Molecular Dynamics Simulations of Amylose- and Cellulose-Based Selectors and Related Enantioseparations in Liquid Phase Chromatography. Molecules, 28.","DOI":"10.3390\/molecules28217419"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1002\/chir.23369","article-title":"Enantioselective Separation of Nonsteroidal Anti-Inflammatory Drugs with Amylose Tris(3-chloro-5-methylphenylcarbamate) Stationary Phase in HPLC with a Focus on Enantiomeric Quality Control in Six Pharmaceutical Formulations Containing Racemic Mixtures or Single Stereoisomers","volume":"33","author":"Cao","year":"2021","journal-title":"Chirality"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1246\/cl.1984.739","article-title":"Useful Chiral Packing Materials for High-Performance Liquid Chromatographic Resolution. Cellulose Triacetate and Tribenzoate Coated on Macroporous Silica Gel","volume":"13","author":"Okamoto","year":"1984","journal-title":"Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0021-9673(01)94414-0","article-title":"Chromatographic Chiral Resolution: XIV. Cellulose Tribenzoate Derivatives as Chiral Stationary Phases for High-Performance Liquid Chromatography","volume":"389","author":"Okamoto","year":"1987","journal-title":"J. Chromatogr. A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/0021-9673(94)00729-S","article-title":"Dimethyl-, Dichloro- and Chloromethylphenylcarbamates of Amylose as Chiral Stationary Phases for High-Performance Liquid Chromatography","volume":"694","author":"Chankvetadze","year":"1995","journal-title":"J. Chromatogr. A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1002\/(SICI)1521-3773(19980504)37:8<1020::AID-ANIE1020>3.0.CO;2-5","article-title":"Polysaccharide Derivatives for Chromatographic Separation of Enantiomers","volume":"37","author":"Okamoto","year":"1998","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"13235","DOI":"10.1021\/acs.chemrev.1c00846","article-title":"Recognition in the Domain of Molecular Chirality: From Noncovalent Interactions to Separation of Enantiomers","volume":"122","author":"Peluso","year":"2022","journal-title":"Chem. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1021\/ac961241l","article-title":"Mechanistic Aspects of Chiral Discrimination Modified Cellulose","volume":"69","author":"Crocker","year":"1997","journal-title":"Anal. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.carres.2017.01.003","article-title":"Discrimination between Naphthacene and Triphenylene using Cellulose Tris(4-methylbenzoate) and Cellulose Tribenzoate: A Computational Study","volume":"439","author":"Murakami","year":"2017","journal-title":"Carbohydr. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.aca.2020.10.050","article-title":"The Molecular Bases of Chiral Recognition in 2-(Benzylsulfinyl)benzamide Enantioseparation","volume":"1141","author":"Peluso","year":"2021","journal-title":"Anal. Chim. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12909","DOI":"10.1002\/slct.201903296","article-title":"Significant Differences in the Energy of X-H\/Pt Interactions between Cisplatin and Transplatin Molecules","volume":"4","year":"2019","journal-title":"ChemistrySelect"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5419","DOI":"10.1063\/1.461658","article-title":"A Theoretical Synthesis of Polymers by using Uniform Localization of Molecular Orbitals: Proposal of an Elongation Method","volume":"95","author":"Imamura","year":"1991","journal-title":"J. Chem. Phys."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7640","DOI":"10.1039\/c2cp24033e","article-title":"An Elongation Method for Large Systems toward Bio-Systems","volume":"14","author":"Aoki","year":"2012","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1007\/s00214-012-1277-9","article-title":"Geometry Optimization for Large Systems by the Elongation Method","volume":"131","author":"Liu","year":"2012","journal-title":"Theor. Chem. Acc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"044110","DOI":"10.1063\/5.0050096","article-title":"Ab Initio Multi-Level Layered Elongation Method and Its Application to Local Interaction Analysis between DNA Bulge and Ligand Molecules","volume":"155","author":"Hisama","year":"2021","journal-title":"J. Chem. Phys."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/0021-9673(94)01039-H","article-title":"Computational Studies on Chiral Discrimination Mechanism of Cellulose Trisphenylcarbamate","volume":"694","author":"Yashima","year":"1995","journal-title":"J. Chromatogr. A"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/0008-6215(87)80122-2","article-title":"\u201cHomogeneous\u201d and \u201cHeterogeneous\u201d Cellulose Tri-esters and a Cellulose Triurethane: Synthesis and Structural Investigations of the Crystalline State","volume":"164","author":"Steinmeier","year":"1987","journal-title":"Carbohydr. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual Molecular Dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graphics"},{"key":"ref_30","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2016). Gaussian 16, Revision A.03, Gaussian, Inc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"13421","DOI":"10.1039\/C8NJ01845F","article-title":"Chiral Separation and a Molecular Modeling Study of Eight Azole Antifungals on the Cellulose Tris(3, 5-dichlorophenylcarbamate) Chiral Stationary Phase","volume":"42","author":"Zhu","year":"2018","journal-title":"New J. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5087","DOI":"10.1002\/pola.21620","article-title":"Preparation of HPLC Chiral Packing Materials using Cellulose Tris(4-methylbenzoate) for the Separation of Chrysanthemate Isomers","volume":"44","author":"Yamamoto","year":"2006","journal-title":"J. Polym. Sci. Part A Polym. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_34","unstructured":"Dennington, R., Keith, T.A., and Millam, J.M. (GaussView, 2016). GaussView, Version 6."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1063\/1.464913","article-title":"Density-Functional Thermochemistry. III. The Role of Exact Exchange","volume":"98","author":"Becke","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1103\/PhysRevB.37.785","article-title":"Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density","volume":"37","author":"Lee","year":"1988","journal-title":"Phys. Rev. B Condens. Matter Mater. Phys."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/0009-2614(89)87234-3","article-title":"Results Obtained with the Correlation Energy Density Functionals of Becke and Lee, Yang and Parr","volume":"157","author":"Miehlich","year":"1989","journal-title":"Chem. Phys. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"26737","DOI":"10.1021\/jp507364h","article-title":"Large-Scale B3LYP Simulations of Ibuprofen Adsorbed in MCM-41 Mesoporous Silica as Drug Delivery System","volume":"118","author":"Corno","year":"2014","journal-title":"J. Phys. Chem. C"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"29082","DOI":"10.1039\/D4CP03600J","article-title":"Insights into the Electronic Structure of Non-steroidal Anti-Inflammatory Drugs: Soft X-ray Study of Fenoprofen, Ketoprofen and Methyl Salicylate in the Gas Phase","volume":"26","author":"Maris","year":"2024","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A Visualization System for Exploratory Research and Analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1002\/jcc.540141112","article-title":"General Atomic and Molecular Electronic Structure System","volume":"14","author":"Schmidt","year":"1993","journal-title":"J. Comput. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1080\/00268977000101561","article-title":"The Calculation of Small Molecular Interactions by the Differences of Separate Total Energies. Some Procedures with Reduced Errors","volume":"19","author":"Boys","year":"1970","journal-title":"Mol. Phys."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"18278","DOI":"10.1021\/acscatal.4c05093","article-title":"Insight into Roles of Rare-Earth Metals in Heterobimetallic Ni\u2013Y Bifunctional Catalysis for Alkyne Semihydrogenation","volume":"14","author":"Su","year":"2024","journal-title":"ACS Catal."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"20216","DOI":"10.1021\/acs.inorgchem.2c03330","article-title":"Mechanism Insights into the Iridium (III)-and B(C6F5)3-Catalyzed Reduction of CO2 to the Formaldehyde Level with Tertiary Silanes","volume":"61","author":"Urriolabeitia","year":"2022","journal-title":"Inorg. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/17\/3503\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:33:19Z","timestamp":1760034799000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/17\/3503"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,26]]},"references-count":45,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["molecules30173503"],"URL":"https:\/\/doi.org\/10.3390\/molecules30173503","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,26]]}}}