Dragos L. Isac , Petru Tîrnovan , Alina Nicolescu , Adrian Fifere , Andrei Neamtu , Mariana Pinteala
{"title":"助溶剂对抗真菌药硝酸丙环唑与β-环糊精络合的影响:分子动力学和核磁共振相结合的研究","authors":"Dragos L. Isac , Petru Tîrnovan , Alina Nicolescu , Adrian Fifere , Andrei Neamtu , Mariana Pinteala","doi":"10.1016/j.ejps.2025.107248","DOIUrl":null,"url":null,"abstract":"<div><div>Understanding the effects of cosolvents in cyclodextrin (CyD)-drug complexation is essential for optimizing drug formulations, as cosolvents influence solubility, stability, and binding affinity. In this study, the inclusion complexation of propiconazole nitrate (PCZH<img>NO₃) with β-cyclodextrin (β-CyD) in mixed dimethyl sulfoxide (DMSO)/water solvent systems was investigated using molecular dynamics (MD) simulations and nuclear magnetic resonance (NMR) spectroscopy. MD simulations revealed that DMSO exhibits a strong affinity for the β-CyD cavity, effectively displacing water molecules even at low concentrations highlighting the competitive nature of DMSO and PCZH<img>NO₃ for inclusion within the β-CyD cavity. Enhanced sampling simulation techniques and potential of mean force (PMF) calculations demonstrated that complexation is most favorable at low DMSO concentrations (∼5 % v/v), with a gradual decrease in binding affinity as DMSO levels increase, ultimately leading to complex destabilization at high DMSO ratios. <sup>1</sup>H-NMR and ROESY spectra confirmed these findings, with chemical shift variations and ROESY cross-peaks indicating a weakening of host-guest interactions with increasing DMSO concentration. The results provide molecular-level insights into the role of cosolvents in modulating drug-CyD interactions, highlighting the need to tailor solvent environments to enhance the stability and efficacy of β-CyD inclusion complexes for pharmaceutical applications.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107248"},"PeriodicalIF":4.7000,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cosolvent effects on the complexation of the antifungal propiconazole nitrate with β-cyclodextrin: A combined molecular dynamics and NMR study\",\"authors\":\"Dragos L. Isac , Petru Tîrnovan , Alina Nicolescu , Adrian Fifere , Andrei Neamtu , Mariana Pinteala\",\"doi\":\"10.1016/j.ejps.2025.107248\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Understanding the effects of cosolvents in cyclodextrin (CyD)-drug complexation is essential for optimizing drug formulations, as cosolvents influence solubility, stability, and binding affinity. In this study, the inclusion complexation of propiconazole nitrate (PCZH<img>NO₃) with β-cyclodextrin (β-CyD) in mixed dimethyl sulfoxide (DMSO)/water solvent systems was investigated using molecular dynamics (MD) simulations and nuclear magnetic resonance (NMR) spectroscopy. MD simulations revealed that DMSO exhibits a strong affinity for the β-CyD cavity, effectively displacing water molecules even at low concentrations highlighting the competitive nature of DMSO and PCZH<img>NO₃ for inclusion within the β-CyD cavity. Enhanced sampling simulation techniques and potential of mean force (PMF) calculations demonstrated that complexation is most favorable at low DMSO concentrations (∼5 % v/v), with a gradual decrease in binding affinity as DMSO levels increase, ultimately leading to complex destabilization at high DMSO ratios. <sup>1</sup>H-NMR and ROESY spectra confirmed these findings, with chemical shift variations and ROESY cross-peaks indicating a weakening of host-guest interactions with increasing DMSO concentration. The results provide molecular-level insights into the role of cosolvents in modulating drug-CyD interactions, highlighting the need to tailor solvent environments to enhance the stability and efficacy of β-CyD inclusion complexes for pharmaceutical applications.</div></div>\",\"PeriodicalId\":12018,\"journal\":{\"name\":\"European Journal of Pharmaceutical Sciences\",\"volume\":\"213 \",\"pages\":\"Article 107248\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-08-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Pharmaceutical Sciences\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0928098725002465\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Pharmaceutical Sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0928098725002465","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Cosolvent effects on the complexation of the antifungal propiconazole nitrate with β-cyclodextrin: A combined molecular dynamics and NMR study
Understanding the effects of cosolvents in cyclodextrin (CyD)-drug complexation is essential for optimizing drug formulations, as cosolvents influence solubility, stability, and binding affinity. In this study, the inclusion complexation of propiconazole nitrate (PCZHNO₃) with β-cyclodextrin (β-CyD) in mixed dimethyl sulfoxide (DMSO)/water solvent systems was investigated using molecular dynamics (MD) simulations and nuclear magnetic resonance (NMR) spectroscopy. MD simulations revealed that DMSO exhibits a strong affinity for the β-CyD cavity, effectively displacing water molecules even at low concentrations highlighting the competitive nature of DMSO and PCZHNO₃ for inclusion within the β-CyD cavity. Enhanced sampling simulation techniques and potential of mean force (PMF) calculations demonstrated that complexation is most favorable at low DMSO concentrations (∼5 % v/v), with a gradual decrease in binding affinity as DMSO levels increase, ultimately leading to complex destabilization at high DMSO ratios. 1H-NMR and ROESY spectra confirmed these findings, with chemical shift variations and ROESY cross-peaks indicating a weakening of host-guest interactions with increasing DMSO concentration. The results provide molecular-level insights into the role of cosolvents in modulating drug-CyD interactions, highlighting the need to tailor solvent environments to enhance the stability and efficacy of β-CyD inclusion complexes for pharmaceutical applications.
期刊介绍:
The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development.
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Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.