JOURNAL OF MOLECULAR GRAPHICS & MODELLING
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2017
·
IF 1.754
Xiuqing Zhang,Ting Liu,Xiaohui Fan,Ni Ai
In silico modeling of blood-brain barrier (BBB) permeability plays an important role in early discovery of central nervous system (CNS) drugs due to its high-throughput and cost-effectiveness. Natural products (NP) have demonstrated considerable therapeutic efficacy against several CNS diseases. However, BBB permeation property of NP is scarcely evaluated both experimentally and computationally. It is well accepted that significant difference in chemical spaces exists between NP and synthetic drugs, which calls into doubt on suitability of available synthetic chemical based BBB permeability models for the evaluation of NP. Herein poor discriminative performance on BBB permeability of NP are first confirmed using internal constructed and previously published drug-derived computational models, which warrants the need for NP-oriented modeling. Then a quantitative structure−property relationship (QSPR) study on a NP dataset was carried out using four different machine learning methods including support vector machine, random forest, Naïve Bayes and probabilistic neural network with 67 selected features. The final consensus model was obtained with approximate 90% overall accuracy for the cross-validation study, which is further taken to predict passive BBB permeability of a large dataset consisting of over 10,000 compounds from traditional Chinese medicine (TCM). For 32 selected TCM molecules, their predicted BBB permeability were evaluated by in vitro parallel artificial membrane permeability assay and overall accuracy for in vitro experimental validation is around 81%. Interestingly, our in silico model successfully predicted different BBB permeation potentials of parent molecules and their known in vivo metabolites. Finally, we found that the lipophilicity, the number of hydrogen bonds and molecular polarity were important molecular determinants for BBB permeability of NP. Our results suggest that the consensus model proposed in current work is a reliable tool for prioritizing potential CNS active NP across the BBB, which would accelerate their development and provide more understanding on their mechanisms, especially those with pharmacologically active metabolites.
研究领域:
药物化学
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计算生物学
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中药学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2020
·
IF 4.845
Shan Huang,Yike Huang,Xiongwei Yin,Dandan Wang,Wei Xiang,Min Wang,Zhining Xia
The absorption mechanisms of drugs play an important role on development and various application of drugs. However, the present methods of absorption mechanisms are not perfect enough. Hence, exploring a novel method to accurately predict the absorption mechanisms is necessary. In this study, we developed an Ussing model coupled with artificial membrane (AM-Ussing) for predicting the permeability of passive diffusion. Furthermore, by the combination of AM-Ussing and Ussing model, the three different mechanisms including efflux transport, uptake transport and passive diffusion could be successfully distinguished. Specifically, 12 drugs of passive transport were selected to evaluate AM-Ussing. And the high permeability correlation between AM-Ussing model and traditional Ussing model indicated that AM-Ussing was successfully established. Moreover, the absorption mechanisms of 11 drugs were predicted by the combination of AM-Ussing and Ussing model. The results showed that three kinds of absorption mechanisms mentioned can be predicted successfully. Therefore, AM-Ussing model is a potential tool to assess passive diffusion, and the combined use of AM-Ussing and Ussing model is an effective method to predict the intestinal absorption mechanisms of drugs.
研究领域:
药剂学
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药理学
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生物药剂学
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产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
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2021
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IF 4.769
Peijie Zhu,Weijia Chen,Qiqin Wang,Huihui Wu,Meng Ruan,Hongwu Wang,Zhengjin Jiang
In this research, a new phospholipid based monolith was fabricated by in situ co-polymerization of 1-dodecanoyl-2-(11-methacrylamidoundecanoyl)- sn -glycero-3-phosphoethanolamine and ethylene dimethacrylate to mimick bio-membrane environment. Excellent physicochemical properties of this novel monolith that were achieved included column efficiency, stability, and permeability. Moreover, the biomimetic monolith showed outstanding separation capability for a series of intact proteins and small molecules. In particular, it exhibited good potential as an alternative to the commercial immobilized artificial membrane (IAM) column (IAM.PC.DD2) for studying drug-membrane interactions. This study not only enriched the types of IAM stationary phases, but also provided a simple model for the prediction of phosphatidylethanolamine related properties of drug candidates.
研究领域:
分析化学
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药物化学
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生物医学工程
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DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2024
·
IF 4.5
Changying Chen,Guoqi Yu,Yanyan Zhou,Hongliang Fu,Wenna Huang,Zhixing Wang,Xiang Luo,Xuguang Yin,Su Mao,Kewu Zhu
Curcumin (CUR) has known to have poor oral bioavailability due to its poor aqueous solubility and stability in gastrointestinal fluid condition as well as its limited permeability which greatly limits its applications in food and medical fields. The present study reported the development of CUR nanocrystal suspension (CUR-NS) for enhanced bioavailability, stabilized with octenyl succinic anhydride modified starch (OSA-S), a naturally renewable and biocompatible biomolecule. This preparation was achieved via an antisolvent precipitation combined with ultrasonic dispersion method, following which the suspension was freeze-dried to form powder CUR nanocrystals (CUR-NCs). Physicochemical properties of the prepared CUR-NS and CUR-NCs powders were extensively characterized. The particle size of the nanocrystals was found to be around 322.8 ± 15.7 nm with a small polydispersity index (PDI) of about 0.230 ± 0.039. Rod like crystal shape was observed by the SEM. Results from powder X-ray diffraction (pXRD) and differential scanning calorimetry (DSC) indicated that the crystal form of CUR in CUR-NCs was a monoclinic polymorph Form 2. Stability results indicated that CUR-NCs possessed an excellent storage-, thermal-, and photo-stabilities. CUR-NCs had a significantly higher dissolution rate, a 68-fold increase in its solubility than that of raw CUR. The cytotoxicity assay demonstrated that CUR-NCs exhibited lower toxicity towards normal human kidney epithelial cells compared to raw CURs. Parallel artificial membrane permeability assay (PAMPA) characterization confirmed that the flux of CUR was significantly enhanced after forming nanocrystals with OSA-S, probably resulting from its increased solubility and dissolution rate. The study showed that OSA-S could effectively stabilize CUR-NCs, and CUR-NCs developed in the current work exhibited significant enhancement in the stability and dissolution rate leading to an improved bioavailability which might be helpful for further development of CUR based products.
研究领域:
药学
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纳米技术
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食品科学
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生物技术
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产品关联
DOI
高影响因子
Pharmaceutics
·
2020
·Vol. 12
·期 2
·144
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IF 4.421
Ziyue Xi,Wei Zhang,Yali Fei,Mingshu Cui,Luyao Xie,Lu Chen,Lu Xu
This work explored absorption efficacy via an in vivo imaging system and parallel artificial membrane penetration in indomethacin (IMC) solid dispersion (SD) systems. Two different polymer excipients—hydroxypropyl methylcellulose (HPMC) and Kollicoat IR as precipitation inhibitors (PIs)—combined with mesoporous silica nanoparticles (MSNs) as carriers were investigated. The IMC–SDs were prepared using the solvent evaporation method and characterized by solubility analysis, infrared (IR) spectroscopy, powder X-ray diffraction (PXRD), field emission scanning electron microscopy (FESEM), and differential scanning calorimetry (DSC). It was confirmed that IMC successfully changed into an amorphous state after loading into the designed carriers. The in vitro release and stability experiments were conducted to examine the in vitro dissolution rates of IMC–SDs combined with HPMC and Kollicoat IR as PIs which both improved approximately three-fold to that of the pure drug. Finally, in vivo studies and in vitro parallel artificial membrane penetration (PAMPA) experiments ensured the greater ability of enhancing the dissolution rates of pure IMC in the gastrointestinal tract by oral delivery. In brief, this study highlights the prominent role of HPMC and Kollicoat IR as PIs in MSN SD systems in improving the bioavailability and gastrointestinal oral absorption efficiency of indomethacin.
研究领域:
药剂学
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药物递送系统
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材料科学
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药代动力学
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DOI
PubMed
高影响因子
AAPS PHARMSCITECH
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2025
·Vol. 26
·期 7
·1-17
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IF 4
Tan Lihua,Jing Zhongli,Li Na,Yu Xuan,Liu Yi,Wang Meng,Ren Xiaoliang
This study introduced a novel vectorized Biopharmaceutics Classification System (BCS) model designed to evaluate the biopharmaceutical properties of active pharmaceutical ingredients (APIs) and their variations under different influencing factors. The model was validated using water-soluble supramolecular p -Sulfonatocalix[n]arenes (SCnA, n = 6, 8), promising pharmaceutical adjuvants, to enhance the solubility and bioavailability of a series of APIs in vitro . The binding interactions of SCnA with 22 alkaloids were assessed for their impact on solubility and permeability using the classical shake-flask method and the parallel artificial membrane permeability assay (PAMPA). To quantify the effects, the change in directional cosine (θ) for each API was calculated by measuring the ratio of the differences in x- and y-coordinates before and after binding. The linear distance and modulus length (r) changes for each API were determined using the Pythagorean theorem, enabling a quantitative assessment of the modifications in solubility and permeability. The potential changes in oral bioavailability pre- and post-binding were visualized using heat maps based on θ and r, highlighting significant improvements in the solubility of compounds such as allicin, tetrandrine, lycorisine, and others. These changes corresponded with shifts in BCS classification, indicating a positive relationship between SCnA concentration, cavity size, and enhanced solubility. The study also evaluated the influence of pH, and concentrations of host and guest, to assess the tolerance of SCnA for further pharmaceutical applications. Based on prior safety assessments, SCnA ( n = 6, 8) demonstrated significant potential as solubilizing excipients. The vectorized BCS model enabled precise, quantitative analysis of biopharmaceutical property variations without added experimental complexity, offering a tool for high-throughput screening of excipients in pharmaceutical formulation and processing. Graphical
研究领域:
药剂学
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药物递送
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生物药剂学
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超分子化学
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药用辅料
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体外研究
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2017
·
IF 3.671
Ke-Lin Chen,Ling Gan,Zhen-Hua Wu,Jin-Fang Qin,Wen-Xia Liao,Huang Tang
A series of 4- substituted sampangine derivatives (4-aminoalkylaminosampangine Ar–NH(CH 2 ) n NR 1 R 2 ) has been designed, synthesized, and tested for their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-myloid (Aβ) aggregation. The synthetic compounds exhibited high AChE inhibitory activity and a significant in vitro inhibitory potency toward the self-induced Aβ aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of Aβ42 secretion levels. Moreover, most of the synthetic compounds were predicted to be able to cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. The result encourages us to study this class of compounds thoroughly and systematically.
研究领域:
药理学
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神经科学
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化学
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DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR LIQUIDS
·
2019
·
IF 4.561
Hao Wu,Zhaizhu Deng,Bijian Zhou,Minghui Qi,Minghuang Hong,Guobin Ren
The aim of this study was to explore the feasibility of transdermal delivery of ibuprofen using ionic liquid technology. Ibuprofen, a non-steroidal anti-inflammatory drug, was transformed into nine ionic liquids using aromatic, tetraalkylammonium and tetraalkylphosphonium cationic counterions . Both the free drug and synthesized ionic liquids were fully characterized by X-ray Powder Diffractometry (XRPD) analysis, thermal analysis, Fourier Transform Infrared Spectroscopy (FT-IR) analysis and Nuclear Magnetic Resonance Spectrometer analysis (NMR), and the aqueous solubility at 25 °C as well as the octanol-water partition coefficients (LogP) were measured. To evaluate transdermal potential, in vitro skin permeation testing was carried out via Skin Parallel Artificial Membrane Permeability Assays (Skin PAMPA). In addition, the potential skin toxicity of ionic liquids was evaluated by determining their cytotoxicity against HaCaT cells. All the synthesized ibuprofen ionic liquids showed improved skin permeability comparing with the conventional sodium salt. Specifically, ionic liquids with didecyldimethylammonium and tetrahexylammonium counterions were significantly more permeable through artificial skin membrane than the free form of ibuprofen. Conductivity test and 2D NMR nuclear Overhauser effect (NOE) techniques corroborated that ionic liquids with stronger intermolecular intermolecular interaction and higher degree of ion association in aqueous environment crossed the artificial skin membrane more rapidly and efficiently. Taken together, ionic liquids technology could be a versatile platform to turn the physicochemical and biological properties of ionizable drugs and facilitate their transdermal delivery .
研究领域:
药剂学
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药物递送
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药物化学
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生物物理学
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产品关联
DOI
高影响因子
CHEMOSPHERE
·
2021
·
IF 7.086
Yan Cao,Linfeng Zhang,Yingxue Geng,Yingjie Li,Qun Zhao,Jianhong Huang,Ping Ning,Senlin Tian
Polycyclic aromatic hydrocarbons (PAHs) can penetrate and accumulate in the pulmonary surfactant (PS) membranes, leading to abnormalities of biological macromolecules and the destruction of membrane structure and properties. In the present study, the bioavailability , apparent permeability, effective permeability and residual coefficient of 10 PAHs on PS membrane was assessed by the parallel artificial membrane permeability assay (PAMPA). The influence of various forces on permeability is obtained by analyzing the correlation between parameters and physicochemical properties . Research shows that octanol-water partition coefficient ( K ow ) cannot directly predict permeability, and permeability has no significant relationship with polarity. Dispersion, induction, coupling/polarization promote permeation, while hydrogen bonded acid and n-n electron pair inhibit permeation. Further surface pressure-area (π-A) isotherms test and Brewster angle microscope observation manifested that there are huge differences in the transmembrane ability and effects on the membrane of PAHs with different structures. This work has considerable significance that will help to evaluate the bioavailability and human health risk of PAHs.
研究领域:
环境科学
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毒理学
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生物物理学
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化学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）