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Discovery and repurposing of artemisinin

《医学前沿（英文）》 2022年第16卷第1期页码 1-9 doi: 10.1007/s11684-021-0898-6

摘要： Malaria is an ancient infectious disease that threatens millions of lives globally even today. The discovery of artemisinin, inspired by traditional Chinese medicine (TCM), has brought in a paradigm shift and been recognized as the “best hope for the treatment of malaria” by World Health Organization. With its high potency and low toxicity, the wide use of artemisinin effectively treats the otherwise drug-resistant parasites and helps many countries, including China, to eventually eradicate malaria. Here, we will first review the initial discovery of artemisinin, an extraordinary journey that was in stark contrast with many drugs in western medicine. We will then discuss how artemisinin and its derivatives could be repurposed to treat cancer, inflammation, immunoregulation-related diseases, and COVID-19. Finally, we will discuss the implications of the “artemisinin story” and how that can better guide the development of TCM today. We believe that artemisinin is just a starting point and TCM will play an even bigger role in healthcare in the 21st century.

关键词： artemisinin drug repurposing cancer inflammation COVID-19 traditional Chinese medicine

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Identification of cancer stem cells provides novel tumor models for drug discovery

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《医学前沿（英文）》 2012年第6卷第2期页码 112-121 doi: 10.1007/s11684-012-0199-1

摘要：

Cancer stem cells (CSCs) have received considerable attention from the research community since they were first reported in human acute myeloid leukemia 15 years ago. Accumulating evidence suggests that CSCs are responsible for tumor initiation and progression, drug resistance, and metastasis in both liquid and solid tumors. These findings lead to the development of novel compounds targeting CSC populations that is becoming increasingly important for eradicating CSCs in heterogeneous tumor masses and to cure the cancer. Since 2003, we have participated in CSC studies and encountered crucial early events in the field. This article reviews the history of CSC biology, clarifies the term and its definition, and further addresses the issue of how to utilize CSCs in therapeutic target discovery and drug development based on our substantial experience.

关键词： cancer stem cell tumor model drug discovery

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DISCOVERY OF TRIKETONE-QUINOXALINE HYBRIDS AS POTENT HPPD INHIBITORS USING STRUCTURE-BASED DRUG DESIGN

《农业科学与工程前沿（英文）》 2022年第9卷第1期页码 133-145 doi: 10.15302/J-FASE-2021401

摘要：

p-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) belongs to the family of Fe(II)-dependent non-heme oxygenases that occur in the majority of aerobic organisms. HPPD has proved to be a promising target in herbicide research and development. A battery of novel triketone-quinoxaline compounds has been designed using a structure-based drug design strategy and then prepared. Enzyme inhibition assays show that these synthesized derivatives possess favorable inhibition capability against Arabidopsis thaliana HPPD with IC₅₀ values ranging from 0.317 to 0.891 μmol·L⁻¹. Subsequently, the molecular docking results indicate that two adjacent carbonyls of the triketone moiety of the representative compound 2-(2,3-dimethyl-8-(o-tolyl)quinoxaline-6-carbonyl)-3-hydroxycyclohex-2-en-1-one (7d) engage in chelation with the ferrous ion of A. thaliana HPPD in a bidentate pose, and its quinoxaline scaffold forms two sets of parallel π-stacking interaction between two phenylalanine residues (Phe424 and Phe381). In addition, the extended phenyl group also interacts with Phe392 in a π-π stacking way. This study indicates that triketone-quinoxaline is a promising scaffold for discovering HPPD inhibitors with substantially increased potency, providing insight into the molecular design of new herbicides.

关键词： herbicide / HPPD / inhibitor / quinoxaline / triketon

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人工智能加速GPCR配体的发现 Review

陈伟, 宋驰, 冷梁, 张三印, 陈士林

《工程（英文）》 2024年第32卷第1期页码 19-29 doi: 10.1016/j.eng.2023.09.011

摘要：

G蛋白偶联受体（GPCR）在多种生理过程中发挥着关键作用，是新药发现的重要靶标。然而，传统的GPCR配体发现方法需要投入大量的时间和资源。人工智能方法的出现为GPCR配体的识别和优化提供了有利的工具，改变了GPCR配体发现的研究方式。本文从数据资源、数据描述、模型设计等方面介绍了如何利用人工智能方法构建GPCR配体发现模型，并分析了人工智能方法在GPCR药物领域的应用；提出了一种基于人工智能方法整合多组学数据的GPCR配体筛选策略；探讨了人工智能方法在GPCR研究领域面临的挑战和未来发展方向。人工智能方法与多学科的交叉融合将提高GPCR配体发现的效率。

关键词： G蛋白偶联受体配体人工智能多组学药物发现

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人工智能在药学领域中的应用 Review

路明坤, 殷佳依, 朱奇, 林高乐, 牟敏杰, 柳扶摇, 潘子祺, 游楠欣, 廉希晨, 李丰成, 张洪宁, 郑玲燕, 张维, 张瀚毓, 沈子豪, 顾臻, 李洪林, 朱峰

《工程（英文）》 2023年第27卷第8期页码 37-69 doi: 10.1016/j.eng.2023.01.014

摘要：

药物研发影响着人类健康的方方面面，并对医药市场有着巨大的影响。然而，由于药物研发（research and development, R&D）过程漫长而复杂，对新药的投资往往收效甚微。随着实验技术和计算机硬件的发展，人工智能（artificial intelligence, AI）近些年来已成为分析大量高维数据的主要工具。生物医学数据规模的爆炸式增长更使得AI得以应用在药物研发的各个阶段。在生物医学大数据的推动下，AI能够更高效、更低成本地发现新药，从而引发了一场药物研发范式的革命。本综述首先简要介绍了药物发现领域常见的人工智能模型，然后总结并深入讨论了这些模型在药物研发各个阶段的具体应用，如靶点发现、药物发现和设计、临床前研究、药物智能制造以及对医药市场的影响。最后，充分讨论了AI在药物研发中的主要局限性，并提出了可能的解决方案。

关键词：人工智能机器学习深度学习靶标识别靶标发现药物设计药物发现

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Taking advantage of drug resistance, a new approach in the war on cancer

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《医学前沿（英文）》 2018年第12卷第4期页码 490-495 doi: 10.1007/s11684-018-0647-7

摘要：

Identification of the driver mutations in cancer has resulted in the development of a new category of molecularly targeted anti-cancer drugs. However, as was the case with conventional chemotherapies, the effectiveness of these drugs is limited by the emergence of drug-resistant variants. While most cancer therapies are given in combinations that are designed to avoid drug resistance, we discuss here therapeutic approaches that take advantage of the changes in cancer cells that arise upon development of drug resistance. This approach is based on notion that drug resistance comes at a fitness cost to the cancer cell that can be exploited for therapeutic benefit. We discuss the development of sequential drug therapies in which the first therapy is not given with curative intent, but to induce a major new sensitivity that can be targeted with a second drug that selectively targets the acquired vulnerability. This concept of collateral sensitivity has hitherto not been used on a large scale in the clinic and holds great promise for future cancer therapy.

关键词： cancer drug resistance genetic screens senescence targeted therapy

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Biodegradable polymethacrylic acid grafted psyllium for controlled drug delivery systems

Ranvijay KUMAR, Kaushlendra SHARMA

《化学科学与工程前沿（英文）》 2013年第7卷第1期页码 116-122 doi: 10.1007/s11705-013-1310-0

摘要： Polymethacrylic acid (PMA) was synthesized on the backbone of psyllium (Psy) by a microwave assisted method to prepare polymeric grafted materials designated as (Psy- -PMA). Various grades of Psy- -PMA were prepared by changing the degree of grafting from 35%–58% and the materials were then made into tablets. Swelling and biodegradability studies of the tablets were carried out. Acetyl salicylic acid was incorporated in the various Psy- -PMA samples and tablets were prepared to study the in vitro drug release in acidic (pH= 4), neutral (pH= 7), and basic (pH= 9) media. In the acidic medium, the swelling was more than 1300%. In addition, the biodegradable Psy- -PMA had the highest drug release in the acidic medium. This may be attributed to Fickian diffusion since the drug and the medium in which it was released have the same acidic nature.

关键词： psyllium acetyl salicylic acid in-vitro drug release swelling biodegradation

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Protein microspheres for pulmonary drug delivery

Yongda SUN,

《化学科学与工程前沿（英文）》 2010年第4卷第1期页码 82-86 doi: 10.1007/s11705-009-0307-1

摘要： A new supercritical fluid (SCF) technique was developed for the preparation of microspheres for pulmonary drug delivery (PDD). This technique, based on the anti-solvent process, has incorporated advanced engineering design features to enable improved control of the particle formation process. Human recombinant insulin (HRI) was used as a model compound to evaluate the efficiency of this SCF process. An aqueous solution of HRI with a co-solvent was sprayed into high pressure carbon dioxide that extracted the solvent and water, leading to a dry fine powder with good particle size distribution and near ideal morphology for pulmonary drug delivery.

关键词： advanced engineering improved pressure aqueous technique

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Semi-solid materials for controlled release drug formulation: current status and future prospects

Michelle TRAN,Chun WANG

《化学科学与工程前沿（英文）》 2014年第8卷第2期页码 225-232 doi: 10.1007/s11705-014-1429-7

摘要： Semi-solid materials represent an important category of inactive ingredients (excipients) of pharmaceutical products. Here we review several common semi-solid polymers currently used in the controlled release formulations of many drugs. These polymers are selected based on their importance and broad scope of application in FDA-approved drug products and include several polysaccharides (cellulose, starch, chitosan, alginate) and carbomers, a group of mucoadhesive synthetic polymers. Glyceride-based polymers used in self-emulsifying drug delivery systems (SEDDS) will also be discussed for its importance in formulating poorly water-soluble drugs. Unique features and advantages of each type of semi-solid materials are discussed and examples of their use in oral delivery of drugs are provided. Finally, future prospects of developing new and better semi-solid excipients are discussed with the objective of facilitating clinical translation.

关键词： controlled release drug delivery semi-solids polymer excipient

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Nanostructured hollow spheres of hydroxyapatite: preparation and potential application in drug delivery

Xiaojing ZHANG, Weixin ZHANG, Zeheng YANG, Zhao ZHANG

《化学科学与工程前沿（英文）》 2012年第6卷第3期页码 246-252 doi: 10.1007/s11705-012-1299-9

摘要： A solvothermal method has been successfully used to prepare nanostructured hydroxyapatite (HA) hollow spheres with average diameters of about 500 nm and shell thicknesses of about 100 nm in a glycerin/water mixed solvent. Transmission electron microscopy (TEM) and field-emission scanning electron microscopy (FESEM) images show that the shells of the HA hollow spheres are actually composed of nanosheets with thicknesses of about 10 nm. By tuning the glycerin/water volume ratio, two other kinds of HA solid spheres with average diameters of about 6 or 20 μm were assembled from nanoflakes. The properties of the different kinds of spheres as drug delivery carriers were evaluated. Ibuprofen (IBU) was chosen as the model drug to load into the HA samples. The nanostructured HA samples showed a slow and sustained release of IBU. The HA hollow spheres exhibited a higher drug loading capacity and more favorable release properties than the HA solid spheres and thus are very promising for controlled drug release applications.

关键词： hydroxyapatite hollow spheres synthesis drug release

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HIGH-PERFORMANCE COMPUTATION AND ARTIFICIAL INTELLIGENCE IN PESTICIDE DISCOVERY: STATUS AND OUTLOOK

《农业科学与工程前沿（英文）》 2022年第9卷第1期页码 150-154 doi: 10.15302/J-FASE-2021419

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靶向膜蛋白的抗体药物开发的新进展 Review

Georgina To’a Salazar, 黄子逸, 张凝艳, 张学光, 安志强

《工程（英文）》 2021年第7卷第11期页码 1541-1551 doi: 10.1016/j.eng.2020.11.013

摘要：

在疾病干预的众多膜蛋白靶标中，G蛋白偶联受体（GPCR）作为人体内最大的膜受体蛋白家族，成为很多药物的重要靶点，其次是离子通道、转运蛋白和激酶等。膜蛋白在细胞信号转导和运输中发挥了关键作用，当前药物研发面临的挑战在于进一步发掘此类膜蛋白的潜在靶点的干预价值，开发治疗性抗体药物。鉴于特异性抗体能够识别膜蛋白的灵敏特性，以及随着基因工程技术的进步，对已有抗体进行加工改造可获得适应多个靶点蛋白的特异性抗体。然而，成功分离特异靶向膜蛋白抗体取决于一系列因素。我们更易研制和识别结构简单且具有长片段胞外区的抗体分子，但对于高难度的靶点蛋白，如GPCR和其他复杂膜蛋白往往难以得到具有活性的候选抗体。目前若要开发针对复杂膜蛋白（如GPCR、离子通道、转运蛋白和激酶）的抗体药物，必须从抗原靶点设计、抗体筛选策略、先导抗体优化及药物研发模式方面进行考虑。深入研究靶标膜蛋白的结构有助于推进治疗性抗体药物的开发进程。本文概述了抗体靶向复杂膜蛋白的优势和挑战，以及膜蛋白抗原制备和抗体研发策略的最新进展。

关键词：抗体治疗复杂膜蛋白离子通道转运蛋白膜结合酶 G蛋白偶联受体药物发现

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Liquid metal material genome: Initiation of a new research track towards discovery of advanced energy

Lei WANG, Jing LIU

《能源前沿（英文）》 2013年第7卷第3期页码 317-332 doi: 10.1007/s11708-013-0271-9

摘要： As the basis of modern industry, the roles materials play are becoming increasingly vital in this day and age. With many superior physical properties over conventional fluids, the low melting point liquid metal material, especially room-temperature liquid metal, is recently found to be uniquely useful in a wide variety of emerging areas from energy, electronics to medical sciences. However, with the coming enormous utilization of such materials, serious issues also arise which urgently need to be addressed. A biggest concern to impede the large scale application of room-temperature liquid metal technologies is that there is currently a strong shortage of the materials and species available to meet the tough requirements such as cost, melting point, electrical and thermal conductivity, etc. Inspired by the Material Genome Initiative as issued in 2011 by the United States of America, a more specific and focused project initiative was proposed in this paper—the liquid metal material genome aimed to discover advanced new functional alloys with low melting point so as to fulfill various increasing needs. The basic schemes and road map for this new research program, which is expected to have a worldwide significance, were outlined. The theoretical strategies and experimental methods in the research and development of liquid metal material genome were introduced. Particularly, the calculation of phase diagram (CALPHAD) approach as a highly effective way for material design was discussed. Further, the first-principles (FP) calculation was suggested to combine with the statistical thermodynamics to calculate the thermodynamic functions so as to enrich the CALPHAD database of liquid metals. When the experimental data are too scarce to perform a regular treatment, the combination of FP calculation, cluster variation method (CVM) or molecular dynamics (MD), and CALPHAD, referred to as the mixed FP-CVM-CALPHAD method can be a promising way to solve the problem. Except for the theoretical strategies, several parallel processing experimental methods were also analyzed, which can help improve the efficiency of finding new liquid metal materials and reducing the cost. The liquid metal material genome proposal as initiated in this paper will accelerate the process of finding and utilization of new functional materials.

关键词： liquid metal material genome energy material material discovery advanced material room-temperature liquid alloy thermodynamics phase diagram

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An econometric investigation using price discovery theory

Yeli ZENG, Cong DONG, Mikael HÖÖK, Jinhua SUN, Danyang SHI

《能源前沿（英文）》 2020年第14卷第4期页码 726-739 doi: 10.1007/s11708-020-0701-4

摘要： China became the world’s second largest liquefied natural gas (LNG) importer in 2018 but has faced extremely high import costs due to a lack of bargaining power. Assessments of the Shanghai LNG Price Index, first released in 2015, are vital for improving the understanding of these cost dynamics. This paper, using the LNG price index data from the Shanghai Petroleum and Gas Exchange (SHPGX) coupled with domestic and international LNG prices from July 1, 2015 to December 31, 2018, estimates several econometric models to evaluate the long-term and short-term equilibriums of the Shanghai LNG Price Index, the responses to market information shocks and the leading or lagging relationships with LNG and alternative energy prices from other agencies. The results show that the LNG price index of the SHPGX has already exhibited a long-term equilibrium and short-term adjustment mechanisms to reflect the average price level and market movements, but the market information transparency and price discovery efficiency of the index are still inadequate. China’s LNG market is still relatively independent of other natural gas markets, and marketization reforms are under way in China. The influence of the SHPGX LNG price index on the trading decisions of market participants is expected to improve with further development of China’s LNG reforms, the formation of a natural gas entry-exit system, and the increasing liquidity of the hub.

关键词： liquefied natural gas price index Shanghai Petroleum and Gas Exchange price discovery market reforms

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Prevalence of antifolate drug resistance markers in in China

《医学前沿（英文）》 2022年第16卷第1期页码 83-92 doi: 10.1007/s11684-021-0894-x

摘要： The dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes of Plasmodium vivax and antifolate resistance-associated genes were used for drug resistance surveillance. A total of 375 P. vivax isolates collected from different geographical locations in China in 2009–2019 were used to sequence Pvdhfr and Pvdhps. The majority of the isolates harbored a mutant type allele for Pvdhfr (94.5%) and Pvdhps (68.2%). The most predominant point mutations were S117T/N (77.7%) in Pvdhfr and A383G (66.8%) in Pvdhps. Amino acid changes were identified at nine residues in Pvdhfr. A quadruple-mutant haplotype at 57, 58, 61, and 117 was the most frequent (57.4%) among 16 distinct Pvdhfr haplotypes. Mutations in Pvdhps were detected at six codons, and the double-mutant A383G/A553G was the most prevalent (39.3%). Pvdhfr exhibited a higher mutation prevalence and greater diversity than Pvdhps in China. Most isolates from Yunnan carried multiple mutant haplotypes, while the majority of samples from temperate regions and Hainan Island harbored the wild type or single mutant type. This study indicated that the antifolate resistance levels of P. vivax parasites were different across China and molecular markers could be used to rapidly monitor drug resistance. Results provided evidence for updating national drug policy and treatment guidelines.

关键词： drug resistance antifolates molecular markers Plasmodium vivax China