JOURNAL OF ORGANIC CHEMISTRY
·
2024
·
IF 3.3
Shuxiong Han,Min Liang,Wenjie Ju,Junrui Wang,Xu Xu,Zhibin Huang,Yingsheng Zhao
This work reports the mild and efficient Ru-catalyzed trifluoroisopropylation of arenes using 2-bromo-1,1,1-trifluoropropane. Various bioactive molecules, such as purine and nucleoside derivatives, were well-suited for this transformation, affording the corresponding products in moderate-to-good yields. This method provides an efficient strategy for synthesizing trifluoroisopropyl molecules for drug discovery.
研究领域:
有机化学
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药物化学
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催化
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DOI
高影响因子
FEBS Open Bio
·
2022
·Vol. 12
·期 10
·1886-1895
·
IF 2.792
Yufang Zhang,Wenkang Li,Yiming Hu,Tianze Ding,Muhammad Mubashar Zafar,Xue Jia,Liya Zhang,Maozhi Ren,Fuguang Li,Wenjing Wang
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading globally for over 2 years, causing serious contagious disease and incalculable damage. The introduction of vaccines has slowed the spread of SARS-CoV-2 to some extent, but there remains a need for specific and effective treatment. The high chemical diversity and safety profiles of natural products make them a potential source of effective anti-SARS-CoV-2 drugs. Cotton plant is one of the most important economic and medical crops and is the source of a large number of antiviral phytochemicals. In this work, we used SARS-CoV-2 main protein (M pro ) as the target to identify potential anti-SARS-CoV-2 natural products in cotton. An in vitro assay showed that of all cotton tissues examined, cotton flower extracts (CFs) exhibited optimal inhibitory effects against M pro . We proceeded to use the CF metabolite database to screen natural M pro inhibitors by combining virtual screening and biochemical assays. We identified that several CF natural products, including astragalin, myricitrin, and astilbin, significantly inhibited M pro with half-maximal inhibitory concentrations (IC50s) of 0.13, 10.73, and 7.92 μ m , respectively. These findings may serve as a basis for further studies into the suitability of cotton as a source of potential therapeutics for SARS-CoV-2.
研究领域:
病毒学
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天然药物化学
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分子药理学
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植物生物技术
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抗病毒治疗
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药物发现
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DOI
高影响因子
ANALYST
·
2012
·Vol. 137
·期 18
·4235-4240
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IF 4.23
Xiaoyu Mu,Li Qi,Ying Shen,Haizhi Zhang,Juan Qiao,Huimin Ma
A novel amino acid ionic liquid (AAIL) with L-ornithine (L-Orn) as anion was successfully synthesized, and subsequently applied as an available chiral ligand coordinated with Zn(II) in a chiral ligand exchange capillary electrophoresis (CLE-CE) system for the enantioseparation of dansyl amino acids (Dns-D,L-AAs). The influence of key parameters, such as buffer pH, concentration ratio of Zn(II) to ligand and complex concentration, was investigated in detail. Eleven pairs of Dns-D,L-AAs enantiomers were baseline separated and three pairs were partly separated under the optimum conditions. For exploring its potential application, the quantitative features of this proposed method were studied. Good linearity (r2 = 0.999) and favorable repeatability (RSD ≤ 3.4%) were obtained by using Dns-D,L-Met as the test analyte. Finally, this method was employed to investigate the inhibition efficiency of D-amino acid oxidase (DAAO) inhibitors, which may pave a new way for the high-throughput screening of enzyme inhibitors and relevant drug discovery.
研究领域:
分析化学
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药物分析
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酶学
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手性分离
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药物发现
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代谢酶
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DOI
高影响因子
Small
·
2022
·Vol. 18
·期 29
·2202622
·
IF 15.153
Hao Zhu,Zixuan Chen,Yun Chen,Jun-Jie Zhu
Quantifying the binding kinetics and affinities of protein–small molecule interactions is critical for biomarker validation, drug discovery, and deep understanding of various biological processes at the molecular-scale. Novel approaches are demanded as most common label-free techniques are mass-sensitive, which are not suitable for the detection of small molecule interactions. Here, an optical imaging platform is developed to measure the binding kinetics of both protein–small molecules and protein–ions based on monolayer MoS 2 , an ultra-thin 2D material whose optical absorption is extremely sensitive to charge. A model is established to calibrate the optical response due to the charged analyte binding and it is applied to quantify the interactions between abl1 kinase and different small-molecule inhibitors. Such a presented method is capable of distinguishing different inhibitors binding to a wild or mutated kinase, which provides guidance for drug evaluation and drug mechanism exploration. The binding kinetics of calcium ions to calmodulin is also measured, further broadening the application field of the method. In addition, the imaging capability allows mapping the local binding kinetics of the molecular interactions with a high resolution, which reveals visible spatial variability and offers a promising tool for studying heterogeneous local interfacial interactions.
研究领域:
分子生物学
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药物发现
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生物传感器
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化学生物学
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生物物理
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转化医学
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纳米生物技术
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DOI
高影响因子
MOLECULAR DIVERSITY
·
2023
·Vol. 28
·期 4
·2429-2447
·
IF 3.8
Li Guo,Li Jiaxuan,Tian Yujia,Zhao Yunyang,Pang Xiaoyang,Yan Aixia
In this study, we built classification models using machine learning techniques to predict the bioactivity of non-covalent inhibitors of Bruton’s tyrosine kinase (BTK) and to provide interpretable and transparent explanations for these predictions. To achieve this, we gathered data on BTK inhibitors from the Reaxys and ChEMBL databases, removing compounds with covalent bonds and duplicates to obtain a dataset of 3895 inhibitors of non-covalent. These inhibitors were characterized using MACCS fingerprints and Morgan fingerprints, and four traditional machine learning algorithms (decision trees (DT), random forests (RF), support vector machines (SVM), and extreme gradient boosting (XGBoost)) were used to build 16 classification models. In addition, four deep learning models were developed using deep neural networks (DNN). The best model, Model D_4, which was built using XGBoost and MACCS fingerprints, achieved an accuracy of 94.1% and a Matthews correlation coefficient (MCC) of 0.75 on the test set. To provide interpretable explanations, we employed the SHAP method to decompose the predicted values into the contributions of each feature. We also used K-means dimensionality reduction and hierarchical clustering to visualize the clustering effects of molecular structures of the inhibitors. The results of this study were validated using crystal structures, and we found that the interaction between the BTK amino acid residue and the important features of clustered scaffold was consistent with the known properties of the complex crystal structures. Overall, our models demonstrated high predictive ability and a qualitative model can be converted to a quantitative model to some extent by SHAP, making them valuable for guiding the design of new BTK inhibitors with desired activity.
研究领域:
计算化学
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药物发现
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生物信息学
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生物学中的机器学习
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结构生物学
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DOI
高影响因子
ANALYTICAL CHEMISTRY
·
2015
·
IF 5.636
Carl Esben Poulsen,Robert C. R. Wootton,Anders Wolff,Andrew J. deMello,Katherine S. Elvira
The determination of pharmacokinetic properties of drugs, such as the distribution coefficient (D) is a crucial measurement in pharmaceutical research. Surprisingly, the conventional (gold standard) technique used for D measurements, the shake-flask method, is antiquated and unsuitable for the testing of valuable and scarce drug candidates. Herein, we present a simple microfluidic platform for the determination of distribution coefficients using droplet-based liquid–liquid extraction. For simplicity, this platform makes use of gravity to enable phase separation for analysis and is 48 times faster and uses 99% less reagents than performing an equivalent measurement using the shake-flask method. Furthermore, the D measurements achieved in our platform are in good agreement with literature values measured using traditional shake-flask techniques. Since D is affected by volume ratios, we use the apparent acid dissociation constant, pK′, as a proxy for intersystem comparison. Our platform determines a pK′ value of 7.24 ± 0.15, compared to 7.25 ± 0.58 for the shake-flask method in our hands and 7.21 for the shake-flask method in the literature. Devices are fabricated using injection molding, the batchwise fabrication time is <2 min per device (at a cost of $1 U.S. per device), and the interdevice reproducibility is high.
研究领域:
药物科学
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微流控技术
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分析化学
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药物发现
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芯片实验室技术
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DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2016
·
IF 2.857
Li Zeng,Guowen Zhang,Suyun Lin,Deming Gong
Inhibition of α-glucosidase activity may suppress postprandial hyperglycemia. The inhibition kinetic analysis showed that apigenin reversibly inhibited α-glucosidase activity with an IC50 value of (10.5 ± 0.05) × 10–6 mol L–1, and the inhibition was in a noncompetitive manner through a monophasic kinetic process. The fluorescence quenching and conformational changes determined by fluorescence and circular dichroism were due to the formation of an α-glucosidase–apigenin complex, and the binding was mainly driven by hydrophobic interactions and hydrogen bonding. The molecular simulation showed that apigenin bound to a site close to the active site of α-glucosidase, which may induce the channel closure to prevent the access of substrate, eventually leading to the inhibition of α-glucosidase. Isobolographic analysis of the interaction between myricetin and apigenin or morin showed that both of them exhibited synergistic effects at low concentrations and tended to exhibit additive or antagonistic interaction at high concentrations.
研究领域:
酶动力学
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分子生物学
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植物化学
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糖尿病研究
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药物发现
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DOI
高影响因子
Chinese Journal of Natural Medicines
·
2016
·Vol. 14
·期 3
·227-231
·
IF 1.382
Jie-Hong LI,Jie-Tao PAN,Yong-Qin YIN
In the present study, two new compounds from Ipomoea cairica were identified and demonstrated to have α-glucosidase inhibitory activity. They were isolated by column chromatography on silica gel and sephadex LH-20 and finally purified by prep-HPLC, with their structures being elucidated by spectroscopic methods, such as 1D- and 2D-NMR and HR-TOF-MS, and chemical methods. Compounds 1 and 2 , named cairicoside A and cairicoside B, were evaluated for α-glucosidase inhibitory activity by the MTT method, with the IC 50 values being 25.3 ± 1.6 and 28.5 ± 3.3 μmol·L −1 , respectively.
研究领域:
植物化学
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天然产物化学
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酶抑制
·
药物发现
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DOI
高影响因子
CURRENT TOPICS IN MEDICINAL CHEMISTRY
·
2002
·Vol. 2
·期 12
·1321-1332
·
IF 0
O.F. Guner
With computer-aided drug design established as an integral part of the lead discovery and optimization process, pharmacophores have become a focal point for conceptualizing and understanding receptor-ligand interactions. In the structure-based design process, pharmacophores can be used to align molecules based on the threedimensional arrangement of chemical features or to develop predictive models (e.g., 3DQSAR) that correlate with the experimental activities of a given training set. Pharmacophores can be also used as search queries for retrieving potential leads from structural databases, for designing molecules with specific desired attributes, or as fingerprints for assessing similarity and diversity of molecules. This review article presents a historical perspective on the evolution and use of the pharmacophore concept in the pharmaceutical, biotechnology, and fragrances industry with published examples of how the technology has contributed and advanced the field.
研究领域:
药物化学
·
计算化学
·
药物发现
·
药学
·
生物信息学
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DOI
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2018
·
IF 3.638
Jie Zhu,Hongyu Yang,Yao Chen,Hongzhi Lin,Qi Li,Jun Mo,Yaoyao Bian,Yuqiong Pei,Haopeng Sun
The cholinergic hypothesis has long been a “polar star” in drug discovery for Alzheimer’s disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC50) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC50 = 101.40 nM). Besides, it inhibited amyloid β-protein self-aggregation by 65.49% at 25 μM. In subsequent in vivo scopolamine-induced AD models, compound 10g obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound 10g as a promising multifunctional agent in the drug discovery process against AD.
研究领域:
药物化学
·
神经药理学
·
药物发现
·
分子对接
·
阿尔茨海默病研究
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DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Yahong Tan,Jinyue Yang,Min Wang,Qi Peng,Yongqi Li,Lifeng Fu,Mengmeng Zhang,Jiang Wu,Guanya Yang,Christopher John Hipolito,Youming Zhang,Jianxun Qi,Yi Shi,Yizhen Yin
Macrocyclic peptides have garnered significant attention as promising drug candidates. However, they typically face challenges in achieving and enhancing cell permeability for access to intracellular targets. In this study, we focused on the de novo screening of macrocyclic peptide inhibitors against the main protease (Mpro) of SARS-CoV-2 and identified novel noncovalently bound macrocyclic peptides that effectively inhibit proteolytic activity. High-resolution crystal structures further revealed molecular interactions between the macrocyclic peptides and Mpro. Subsequently, a specific macrocyclic peptide lacking cell permeability was further optimized and transformed into a low-toxicity, metabolically stable bicyclic peptide with a cell penetration capacity and therapeutic potential against SARS-CoV-2. The bicyclic peptide was achieved using a novel strategy that involved introducing both a bicyclic structure and a bridging perfluorobiphenyl group. Our study not only provides a lead peptide inhibitor for COVID-19 but also offers valuable insights into achieving cell penetration for macrocyclic peptides through strategic modifications.
研究领域:
药理学
·
病毒学
·
药物发现
·
蛋白质工程
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DOI
高影响因子
Chemical Biology & Drug Design
·
2020
·Vol. 97
·期 3
·565-571
·
IF 2.548
Bin Sun,Jiahao Wang,Luohua Liu,Longfei Mao,Lizeng Peng,Yuwei Wang
A series of indirubin derivatives hydrochloride were obtained using a convenient and mild method from indirubin. The newly synthesized compounds and their derivatives were characterized by 1 H NMR, 13 C NMR, and MS. Furthermore, we tested their IDO1 enzyme inhibitory activity and anti-proliferative activities in K562 tumor cells. The experimental results revealed that some of the compounds showed potential anti-enzyme and anti-tumor activity. Among of them, compound 4b exhibited certain inhibitory activity on IDO1 (IC 50 : 29.52 μmol/L), and compound 4a displayed activity similar to indirubin in K562 tumor cells (IC 50 : 24.96 μmol/L). This type of indirubin derivative is expected to have the potential to act as an immunologically active anti-tumor drug, indicating that further research will be worthwhile.
研究领域:
药物化学
·
肿瘤学
·
药理学
·
药物发现
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）