{"title":"人血清白蛋白与可卡因和古柯碱的生物物理研究:在模拟生理条件下了解药物与蛋白质之间的相互作用","authors":"","doi":"10.1016/j.molliq.2024.125570","DOIUrl":null,"url":null,"abstract":"<div><p>In this study, HSA was used as a transport protein model to simulate the transport dynamics and availability of cocaine (COC) and its pharmacologically active metabolite, cocaethylene (CE). In the interaction studies between the alkaloids and HSA, the binding constant (K<sub>b</sub>) values were higher for CE (2.92 to 8.33 × 10<sup>4</sup> M<sup>−1</sup>) than COC (1.15 to 3.77 × 10<sup>4</sup> M<sup>−1</sup>) at different temperatures. Thermodynamic parameter calculations indicate that COC preferentially interacts through van der Waals forces and hydrogen bonds, while CE interacts hydrophobically. Competition studies using the ANS probe confirmed the more hydrophobic characteristics of CE. Synchronized fluorescence indicated that both compounds preferentially interact in the microregion of the Trp214 residue. Based on 3D fluorescence, UV–vis, and circular dichroic results, changes in the secondary structure of the protein were confirmed. Studies to assess the HSA binding site were carried out using warfarin (site I), diazepam (site II), and digitoxin (subdomain IIIB) as markers, and it was verified that both compounds interact preferentially at the site I. Finally, based on the <sup>1</sup>H NMR and theoretical studies, it was possible to propose the alkaloid epitope in the interaction with HSA. In conclusion, when compared to COC, CE presented greater HSA protein affinity, justifying its longer plasma lifetime and increasing the drug’s effects on the body.</p></div>","PeriodicalId":371,"journal":{"name":"Journal of Molecular Liquids","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Biophysical studies of human serum albumin with cocaine and cocaethylene: Understanding the drug-protein interaction in simulated physiological conditions\",\"authors\":\"\",\"doi\":\"10.1016/j.molliq.2024.125570\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>In this study, HSA was used as a transport protein model to simulate the transport dynamics and availability of cocaine (COC) and its pharmacologically active metabolite, cocaethylene (CE). In the interaction studies between the alkaloids and HSA, the binding constant (K<sub>b</sub>) values were higher for CE (2.92 to 8.33 × 10<sup>4</sup> M<sup>−1</sup>) than COC (1.15 to 3.77 × 10<sup>4</sup> M<sup>−1</sup>) at different temperatures. Thermodynamic parameter calculations indicate that COC preferentially interacts through van der Waals forces and hydrogen bonds, while CE interacts hydrophobically. Competition studies using the ANS probe confirmed the more hydrophobic characteristics of CE. Synchronized fluorescence indicated that both compounds preferentially interact in the microregion of the Trp214 residue. Based on 3D fluorescence, UV–vis, and circular dichroic results, changes in the secondary structure of the protein were confirmed. Studies to assess the HSA binding site were carried out using warfarin (site I), diazepam (site II), and digitoxin (subdomain IIIB) as markers, and it was verified that both compounds interact preferentially at the site I. Finally, based on the <sup>1</sup>H NMR and theoretical studies, it was possible to propose the alkaloid epitope in the interaction with HSA. In conclusion, when compared to COC, CE presented greater HSA protein affinity, justifying its longer plasma lifetime and increasing the drug’s effects on the body.</p></div>\",\"PeriodicalId\":371,\"journal\":{\"name\":\"Journal of Molecular Liquids\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.3000,\"publicationDate\":\"2024-07-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Molecular Liquids\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0167732224016295\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Molecular Liquids","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0167732224016295","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
引用次数: 0
摘要
本研究使用 HSA 作为转运蛋白模型,模拟可卡因(COC)及其药理活性代谢物古柯乙烯(CE)的转运动力学和可用性。在生物碱与 HSA 的相互作用研究中,在不同温度下,CE 的结合常数 (K) 值(2.92 至 8.33 × 10 M)高于 COC(1.15 至 3.77 × 10 M)。热力学参数计算表明,COC 主要通过范德华力和氢键相互作用,而 CE 则通过疏水作用。使用 ANS 探针进行的竞争研究证实了 CE 更疏水的特性。同步荧光表明,这两种化合物都优先在 Trp214 残基的微区相互作用。根据三维荧光、紫外可见光和圆二色性结果,证实了蛋白质二级结构的变化。以华法林(位点 I)、地西泮(位点 II)和地高辛(子域 IIIB)为标记,对 HSA 结合位点进行了评估研究,结果证实这两种化合物都优先在位点 I 发生相互作用。总之,(与 COC 相比)CE 具有更强的 HSA 蛋白亲和力,因此其血浆寿命更长,对人体的药效也更强。
Biophysical studies of human serum albumin with cocaine and cocaethylene: Understanding the drug-protein interaction in simulated physiological conditions
In this study, HSA was used as a transport protein model to simulate the transport dynamics and availability of cocaine (COC) and its pharmacologically active metabolite, cocaethylene (CE). In the interaction studies between the alkaloids and HSA, the binding constant (Kb) values were higher for CE (2.92 to 8.33 × 104 M−1) than COC (1.15 to 3.77 × 104 M−1) at different temperatures. Thermodynamic parameter calculations indicate that COC preferentially interacts through van der Waals forces and hydrogen bonds, while CE interacts hydrophobically. Competition studies using the ANS probe confirmed the more hydrophobic characteristics of CE. Synchronized fluorescence indicated that both compounds preferentially interact in the microregion of the Trp214 residue. Based on 3D fluorescence, UV–vis, and circular dichroic results, changes in the secondary structure of the protein were confirmed. Studies to assess the HSA binding site were carried out using warfarin (site I), diazepam (site II), and digitoxin (subdomain IIIB) as markers, and it was verified that both compounds interact preferentially at the site I. Finally, based on the 1H NMR and theoretical studies, it was possible to propose the alkaloid epitope in the interaction with HSA. In conclusion, when compared to COC, CE presented greater HSA protein affinity, justifying its longer plasma lifetime and increasing the drug’s effects on the body.
期刊介绍:
The journal includes papers in the following areas:
– Simple organic liquids and mixtures
– Ionic liquids
– Surfactant solutions (including micelles and vesicles) and liquid interfaces
– Colloidal solutions and nanoparticles
– Thermotropic and lyotropic liquid crystals
– Ferrofluids
– Water, aqueous solutions and other hydrogen-bonded liquids
– Lubricants, polymer solutions and melts
– Molten metals and salts
– Phase transitions and critical phenomena in liquids and confined fluids
– Self assembly in complex liquids.– Biomolecules in solution
The emphasis is on the molecular (or microscopic) understanding of particular liquids or liquid systems, especially concerning structure, dynamics and intermolecular forces. The experimental techniques used may include:
– Conventional spectroscopy (mid-IR and far-IR, Raman, NMR, etc.)
– Non-linear optics and time resolved spectroscopy (psec, fsec, asec, ISRS, etc.)
– Light scattering (Rayleigh, Brillouin, PCS, etc.)
– Dielectric relaxation
– X-ray and neutron scattering and diffraction.
Experimental studies, computer simulations (MD or MC) and analytical theory will be considered for publication; papers just reporting experimental results that do not contribute to the understanding of the fundamentals of molecular and ionic liquids will not be accepted. Only papers of a non-routine nature and advancing the field will be considered for publication.