作者: Kim, Sunghwan ; Ross, Dylan H. ; Xu, Libin ; Schymanski, Emma L. ; Aurich, Dagny ; Bolton, Evan E. ; Zhang, Jian ; Baker, Erin S. ; Grouès, Valentin ; Dodds, James N. ; Krinsky, Allison M. ; Thiessen, Paul A. ; Elapavalore, Anjana

Finding relevant chemicals in the vast (known) chemical space is a major challenge for environmental and exposomics studies leveraging nontarget high resolution mass spectrometry (NT-HRMS) methods. Chemical databases now contain hundreds of millions of chemicals, yet many are not relevant. This article details an extensive collaborative, open science effort to provide a dynamic collection of chemicals for environmental, metabolomics, and exposomics research, along with supporting information about their relevance to assist researchers in the interpretation of candidate hits. The PubChemLite for Exposomics collection is compiled from ten annotation categories within PubChem, enhanced with patent, literature and annotation counts, predicted partition coefficient (logP) values, as well as predicted collision cross section (CCS) values using CCSbase. Monthly versions are archived on Zenodo under a CC-BY license, supporting reproducible research, and a new interface has been developed, including historical trends of patent and literature data, for researchers to browse the collection. This article details how PubChemLite can support researchers in environmental and exposomics studies, describes efforts to increase the availability of experimental CCS values, and explores known limitations and potential for future developments. The data and code behind these efforts are openly available. PubChemLite can be browsed at https://pubchemlite.lcsb.uni.lu.

2025-01-05·Journal of Computational Chemistry

CGPDTA: An Explainable Transfer Learning‐Based Predictor With Molecule Substructure Graph for Drug‐Target Binding Affinity

Article

作者: Shen, Jun ; Chen, Yadong ; Zhang, Simeng ; Ning, Xiangzhen ; Zhang, Yanmin ; Liu, Yingxu ; Han, Weijie ; Xu, Chengcheng ; Liu, Haichun ; Fan, Qing

ABSTRACTIdentifying interactions between drugs and targets is crucial for drug discovery and development. Nevertheless, the determination of drug‐target binding affinities (DTAs) through traditional experimental methods is a time‐consuming process. Conventional approaches to predicting drug‐target interactions (DTIs) frequently prove inadequate due to an insufficient representation of drugs and targets, resulting in ineffective feature capture and questionable interpretability of results. To address these challenges, we introduce CGPDTA, a novel deep learning framework empowered by transfer learning, designed explicitly for the accurate prediction of DTAs. CGPDTA leverages the complementarity of drug–drug and protein–protein interaction knowledge through advanced drug and protein language models. It further enhances predictive capability and interpretability by incorporating molecular substructure graphs and protein pocket sequences to represent local features of drugs and targets effectively. Our findings demonstrate that CGPDTA not only outperforms existing methods in accuracy but also provides meaningful insights into the predictive process, marking a significant advancement in the field of drug discovery.

2024-12-01·Bioorganic Chemistry

Sodium cromoglycate exerts anti-pulmonary fibrosis effects by targeting the Keap1 protein to activate Nrf2 signaling

Article

作者: Huang, Yuwei ; Yuan, Lei ; Li, Yanchun ; Wang, Chuncheng ; Ma, Chao ; Liu, Xiaofeng ; Ma, Enlong ; Zhao, Xianchen ; Guan, Yingjun

Oxidative stress has been confirmed to be closely related to the occurrence and development of pulmonary fibrosis (PF). The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid-2 related factor 2 (Nrf2) pathway plays a key role in maintaining cellular redox homeostasis. Targeting the Keap1 protein to activate Nrf2 could be a promising strategy for treating PF. Virtual screening via a pharmacophore model was used to screen candidate compounds with potential Keap1 binding ability from the U.S. Food and Drug Administration (FDA) database. The results revealed that sodium cromoglycate (Cro) has the highest fit value and absolute docking score and could improve the thermal stability of the Keap1 protein in a CETSA, confirming that Cro could bind to the Keap1 protein directly. Further studies revealed that Cro promoted Nrf2 translocation into the nucleus, relieved oxidative stress, prevented the epithelial-mesenchymal transition (EMT) process and upregulated fibrosis markers in TGF-β1-induced A549 cells, indicating that Cro has anti-pulmonary fibrosis activity in an in vitro lung fibrosis model. Moreover, in a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, Cro administration improved pulmonary fibrosis, activated Nrf2 signaling, and blocked the EMT process. In summary, these results demonstrated that Cro could activate Nrf2 signaling to clear reactive oxygen species (ROS) by directly binding to Keap1 and alleviate pulmonary fibrosis by blocking the progression of EMT both in vitro and in vivo.

项与阿西美辛相关的新闻（医药）

2024-03-05

·精准药物

含吲哚药物结构与靶点，药理与SAR 研究归纳

吲哚是一种芳香杂环分子，具有一个苯环和一个含氮吡咯环组成的双环结构。吲哚中的氮原子提供一对孤对电子，形成共轭体系，从而稳定了吲哚结构。这对孤电子使吲哚化合物呈现弱碱性(pKa=16.2和pK,=17.6)。由于吡咯环的电子密度相对较高以及氮原子的共轭效应，吲哚可以在其吡咯环的3位发生亲电取代反应(图la)。图 1 (a) 全球有超过70种含有吲哚的合成药物在市场上销售，并被证明具有良好的医疗效果(图1b)。用于治疗的疾病包括糖尿病、癌症、白血病、丙型肝炎、心理障碍和其他临床问题。自2015年起，美国(FDA)专门批准了14种含吲哚药物，其中3种是在2021年批准的(图2)。二氢麦角胺(DHE,1)的化学结构中含有吲哚支架，对头颅血管平滑肌中的5-HT1b受体具有激动活性，治疗偏头痛。昂丹司琼(2)是一种血清素5-HT3受体拮抗剂，用于预防癌症治疗期间和手术后的恶心和呕吐(图3a)。图 3 (a) 双氢麦角胺（1）和昂丹司琼（2）的结构。(b) 双氢麦角胺(1)与其靶点（左）和昂丹司琼(2)与其靶点（右）的关键靶点相互作用。替加色罗(3)在临床相关水平上被认为是5-HT(4)受体的激动剂和5-HT(2B)受体的拮抗剂，其作用之一是使受损的胃肠道运动恢复正常。多拉司琼(4)用于中度致吐的癌症化疗以及术后恶心和呕吐的治疗(图5)。它是一种高效、选择性的血清素5-HT3受体拮抗剂。 Tropisetron（5）可抑制5HT3受体上血清素的活性，从而抑制放疗和化疗引起的呕吐。 Vilazodone(6)是5HT-1A受体的部分激动剂，专门抑制中枢神经系统对血清素的再摄取。在治疗偏头痛急性发作方面，三苯氧胺药物(5-羟色胺受体激动剂)比其他药物更有效、更耐受。这类药物具有起效快、用药时间长、不良反应少等优点。Sumatriptan(7),zolmitriptan(8),naratriptan(9), rizatriptan(10), almotriptan (11), frovatriptan (12), eletriptan (13), 和 oxitriptan (14) 是国外已商业化的曲坦类药物的代表。(图7)。环氧化酶(COX)被称为前列腺素G/H合成酶，而吲哚美辛是一种非特异性的可逆性环氧化酶抑制剂。吲哚美辛(18)属于吲哚-3-乙酸类，其官能团包括对氯苯甲酰基、甲基和甲氧基。它是一种非甾体抗炎药(NSAID), 具有消炎、镇痛和解热的特点(图11a)。 Acemetacin(19)是另一种强效非甾体抗炎药物，由吲哚-3-乙酸衍生而来(图12)。它主要通过酯分解代谢为吲哚美辛。 Etodolac(20)是一种非甾体抗炎药，具有消炎、镇痛和解热作用(图13a)。以前被认为是一种非选择性COX抑制剂，但现在被认为对COX-2的选择性是COX-1的5-50倍。 Carprofen(21)是兽医用作缓解老年犬关节炎症状的辅助疗法的一种非甾体抗炎药，人们认为卡洛芬(21)的作用机制是抑制环氧化酶的活性。帕金森病的药物 Cabergoline(22)是一种长效多巴胺受体激动剂，与D2受体有很强的亲和力，用于治疗高催乳素血症和帕金森综合症(图14a)。 Lisuride(23)可能是某些血清素受体的激动剂,也可能是多巴胺D1受体的拮抗剂。可降低催乳素水平，适量服用可阻止偏头痛，从药理上讲，(23)是还是一种帕金森氏症药物。治疗子宫脱垂的药物甲基麦角新碱(26)是一种麦角生物碱，临床上用于预防和治疗产后和流产后出血(图17)。这种药物与多巴胺D1受体结合，作为一种拮抗剂发挥作用，可增强平滑肌的张力、节奏和节律性收缩的幅度。治疗精神疾病的药物 sertindole（27）是一种抗精神分裂症药物，也是一种苯基吲哚衍生物。临床试验证实，(27)对低水平的多巴胺D2占位具有疗效。治疗神经系统疾病的药物吲哚洛尔(28)是一种非选择性β肾上腺素受体拮抗剂，用于治疗心房颤动、水肿、高血压和室性心动过速。卡维地洛(29)通过阻断β肾上腺素受体防止运动引起的心动过速，它对α-1肾上腺素能受体的作用可使血管平滑肌放松，从而降低外周血管阻力和血压。尼麦角林(30)是一种半合成麦角衍生物，可用于治疗认知功能障碍。这种药剂作为一种选择性α-1A肾上腺素能受体抑制剂用于临床(图20)。治疗生殖系统疾病的药物麦角新碱(32)是一种麦角生物碱，可用于控制妇女的产后和流产后出血。结构与活性关系明确的药物 Tezacaftor(41)属于用于治疗囊性纤维化(CFTR)增效剂。美国食品及药物管理局批准该药与ivacaftor联合用于治疗囊性纤维化(图28a)。该药物可在2至4小时内达到血浆浓度峰值。 2015年2月23日，FDA批准口服去乙酰化酶(DAC)抑制剂Panobinostat(42)用于治疗多发性骨髓瘤(图29a)。(42)在体外与人体血浆蛋白的结合率约为90%,这与其浓度无关。其吲哚环可以通过与Asn645的氢键相互作用为SAR创造一个稳定的框架(图29b)。结构与活性关系不完全明确的药物 Metergoline(52)是一种麦角衍生物，用于治疗女性高催乳素闭经症(图39)。通过靶向钠通道而非5HT受体来抑制钠通道的活性，从而导致泌乳素分泌减少。 Lurbinectedin(53)是一种抗癌天然产物。该药物在化疗中用于治疗转移性小细胞肺癌。Lurbinectedin(53)在临床试验中的治疗反应率和持续时间在2020年获得了加速批准。总体而言，在FDA批准的药物中，含有吲哚环的药物数量在不断增加。在药物分子中引入吲哚砌块也已成为药物化学和药物设计中的一种常见策略。现有的含吲哚药物因其特殊的结构，在抗癌、抗炎和抗病毒等方面具有显著的临床价值。参考文献：DOI: 10.1039/d3md00677h 内容来源于网络，如有侵权，请联系删除。

上市批准放射疗法

100 项与阿西美辛相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D01582	阿西美辛	M01AB11	DB13783

研发状态

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
滑囊炎	中国	佛山市华普生药业有限公司	1996-01-01
疼痛	中国	佛山市华普生药业有限公司	1996-01-01
肌腱病	中国	佛山市华普生药业有限公司	1996-01-01
骨关节炎	日本	Kowa Co., Ltd.	1992-07-10
肩周炎	日本	Kowa Co., Ltd.	1992-07-10
腰痛	日本	Kowa Co., Ltd.	1992-03-16
肌肉骨骼系统疾病	日本	Kowa Co., Ltd.	1992-03-16
术后疼痛	日本	Kowa Co., Ltd.	1992-03-16
呼吸道感染	日本	Kowa Co., Ltd.	1992-03-16
创伤和损伤	日本	Kowa Co., Ltd.	1992-03-16
强直性脊柱炎	德国	Meda Pharma GmbH	1980-01-01
痛风	德国	Meda Pharma GmbH	1980-01-01
关节疾病	德国	Meda Pharma GmbH	1980-01-01
类风湿关节炎	德国	Meda Pharma GmbH	1980-01-01
血栓性静脉炎	德国	Meda Pharma GmbH	1980-01-01