{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T15:31:12Z","timestamp":1787758272191,"version":"build-2784847793"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"State Key Laboratory of Drug Regulatory Science Project","award":["2025SKLDRS0313"],"award-info":[{"award-number":["2025SKLDRS0313"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Rotigotine is a conformationally flexible chiral dopamine agonist, but its solution-phase chiroptical behavior and conformational heterogeneity have not been systematically assessed. This study characterized its electronic circular dichroism (ECD), optical rotatory dispersion (ORD), and vibrational circular dichroism (VCD) responses and evaluated their consistency with its absolute configuration. Methods: ECD and ORD data were acquired for rotigotine ((S)-1) and its simplified analog (S)-2 in acetonitrile and methanol, and VCD spectra were recorded in appropriate deuterated solvents. Conformational searches, Boltzmann weighting, and density functional theory\/time-dependent density functional theory calculations were performed. A principal-component-analysis\/torsion (PCA-Tor) workflow selected a compact but structurally representative conformer ensemble for (S)-1. Results: In acetonitrile, (S)-1 exhibited a positive Cotton effect (CE) at 208.5 nm and a negative CE at 194.0 nm. The Boltzmann-weighted ECD spectrum reproduced the intense negative band below 200 nm and the positive band near 210 nm. The calculated VCD spectrum agreed with the signs and positions of the main experimental bands in the 1500\u20131100 cm\u22121 region. Experimental ORD curves of both compounds were negative in acetonitrile and methanol. The calculations reproduced the sign and overall trend, although their magnitudes were protocol- and population-sensitive. Ring puckering strongly affected the calculated ECD and ORD data, whereas side-chain flexibility expanded the accessible conformational space. Conclusions: The combined results support the known S configuration of rotigotine and demonstrate the value of representative conformational sampling for flexible chiral pharmaceuticals. This study also defines the practical utility and limitations of simplified molecular models in chiroptical analysis.<\/jats:p>","DOI":"10.3390\/ph19091351","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T15:04:32Z","timestamp":1787756672000},"page":"1351","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Representative Conformational Sampling for Chiroptical Analysis of the Flexible Dopamine Agonist Rotigotine"],"prefix":"10.3390","volume":"19","author":[{"given":"Yi-Xuan","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Digestive Health, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3411-4335","authenticated-orcid":false,"given":"Xiao-Li","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Regulatory Science, National Institutes for Drug Control, Beijing 102629, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Wen","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Regulatory Science, National Institutes for Drug Control, Beijing 102629, China"},{"name":"Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digestive Health, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You-Yang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Regulatory Science, National Institutes for Drug Control, Beijing 102629, China"},{"name":"Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-You","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digestive Health, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang-Peng","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digestive Health, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Xin","family":"Tan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digestive Health, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Xiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digestive Health, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei-Bei","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digestive Health, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9496-2280","authenticated-orcid":false,"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Digestive Health, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3455-0216","authenticated-orcid":false,"given":"Li-Hui","family":"Yin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Regulatory Science, National Institutes for Drug Control, Beijing 102629, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1002\/bdd.517","article-title":"Drug disposition in three dimensions: An update on stereoselectivity in pharmacokinetics","volume":"27","author":"Brocks","year":"2006","journal-title":"Biopharm. 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