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喹啉酮类BRD4抑制剂的3D-QSAR研究

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广州化学 2024年第1期49卷 56-61,I0003页

作者：刘亚平程平张淑平上海理工大学材料与化学学院上海200093

使用比较分子力场分析法(CoMFA)和比较分子相似性指数法(CoMSIA)对33个已报道的喹啉酮类BRD4抑制剂进行3D-QSAR模型建立,研究了其化学结构和生物活性间的关系,并用计算机辅助药物设计(computer-aided drug design,CADD)设计出7个喹啉酮... 详细信息

使用比较分子力场分析法(CoMFA)和比较分子相似性指数法(CoMSIA)对33个已报道的喹啉酮类BRD4抑制剂进行3D-QSAR模型建立,研究了其化学结构和生物活性间的关系,并用计算机辅助药物设计(computer-aided drug design,CADD)设计出7个喹啉酮类抑制剂。结果表明,建立的CoMFA(q^(2)=0.926,r^(2)=0.997,r^(2)_(pred)=0.744)和CoMSIA(q^(2)=0.939,r^(2)=0.991,r^(2)_(pred)=0.786)模型具有较好的预测能力,基于这些模型设计的7个新喹啉酮类BRD4抑制剂具有高活性,并对其进行admet性质评价和类药性分析。以上研究结果有助于改造和开发更加有效的喹啉酮类BRD4抑制剂。

关键词：喹啉酮 BRD4抑制剂 3D-QSAR CoMFA CoMSIA admet 类药性

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面向知识发现的药物admet情报预测方法

情报科学 2023年第2期41卷 95-100,156页

作者：郭勇罗敏幸芮中南大学商学院长沙410083

【目的/意义】挖掘药物筛选工作中的隐性知识,借助机器学习的预测能力替代生物实验方法,减少制药流程的研发时间和经济成本。【方法/过程】提出一种面向知识发现的admet情报预测理论框架,以4种传统机器学习方法和2种集成学习方法,分别构... 详细信息

【目的/意义】挖掘药物筛选工作中的隐性知识,借助机器学习的预测能力替代生物实验方法,减少制药流程的研发时间和经济成本。【方法/过程】提出一种面向知识发现的admet情报预测理论框架,以4种传统机器学习方法和2种集成学习方法,分别构建6种分类预测模型,提取药物的隐性知识,比较不同模型的优越性,评估最优模型的经济价值。【结果/结论】以药物分子描述符信息预测admet具有可行性,6种模型性能表现综合排序结果为随机森林、梯度提升决策树、Logistic回归、支持向量机、K近邻、高斯朴素贝叶斯。前沿信息技术能够有效应用于药物知识发现,信息经济学分析可预见创造可观收益,是未来制药工艺降本增效的重要手段。【创新/局限】未来应融合专家知识、追加试验验证、丰富参考指标。

关键词：机器学习情报预测知识发现 admet 经济价值

基于图注意力网络的药物admet分类预测模型构建方法

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数据分析与知识发现 2021年第8期5卷 76-85页

作者：顾耀文张博文郑思杨丰春李姣中国医学科学院/北京协和医学院医学信息研究所北京100020 晶泰科技人工智能研发中心北京100089

【目的】对药物的吸收、分布、代谢、排泄、毒性(Absorption,Distribution,Metabolism,Excretion,Toxicity,admet)中的代谢、毒性属性进行建模,用于虚拟筛选中的药物性质评价。【方法】提出一种图注意力网络构建药物admet预测模型,基于... 详细信息

【目的】对药物的吸收、分布、代谢、排泄、毒性(Absorption,Distribution,Metabolism,Excretion,Toxicity,admet)中的代谢、毒性属性进行建模,用于虚拟筛选中的药物性质评价。【方法】提出一种图注意力网络构建药物admet预测模型,基于开放数据库和科学文献的药物admet数据构造分子图作为分子结构特征,进一步将提出的模型与三种机器学习模型和两种传统的图神经网络模型进行性能比较。【结果】收集整合得到9个admet数据集共计149 457条数据。基于图注意力网络的admet预测模型在9个数据集中的平均准确率为0.825、平均F1分数为0.672。与机器学习和图神经网络基线模型相比,所提方法在平均准确率和平均F1分数指标上最大提升幅度达6.4%和26.0%。【局限】数据清洗步骤可以精细化处理,模型预测性能可以通过改进预训练策略进一步提升。【结论】所提图注意力网络模型在药物admet分类预测上取得良好性能,可将其应用于虚拟药物筛选流程,为计算机辅助药物设计和药物发现提供参考。

关键词：图神经网络图注意力网络多源异构数据 admet 虚拟筛选

Oligomers from the Synthetic Polymers:Another Potential Iceberg of New Pollutants

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Environment & Health 2023年第4期1卷 228-235页

作者： Changzhi Shi Mengjing Wang Zimeng Wang Guangbo Qu Wei Jiang Xiangcheng Pan Mingliang Fang Department of Environmental Science and Engineering Fudan UniversityShanghai 200433China School of Energy and Environment and State Key Laboratory of Marine Pollution City University of Hong KongHong Kong 999077China State Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Environmental SciencesChinese Academy of SciencesBeijing 100085China State Key Laboratory of Pollution Control and Resources Reuse School of the EnvironmentNanjing UniversityNanjing 210023China State Key Laboratory of Molecular Engineering of Polymers Department of Macromolecular ScienceFudan UniversityShanghai 200438China Institute of Eco-Chongming Shanghai 202162China

Pollution generated by synthetic polymers,particularly plastics,has become a significant global environmental problem.However,when compared to polymer-derived products like microplastics,oligomers have not received the attention they deserve.Oligomers are by-products of polymer production and intermediates of degradation.Despite the industrial advancements leading to an exponential increase in the production of new polymers,a majority of oligomers have remained inadequately researched.While the exposure and toxic effects of polylactic acid oligomers have been documented,the structures and fundamental properties of oligomers derived from most polymers are still poorly understood.This knowledge gap presents challenges in establishing effective analytical methods.Considering the potential of oligomers to act as new pollutants,it is imperative to investigate their environmental behavior,as well as their absorption,distribution,metabolism,excretion,and toxicity(admet)properties.This perspective highlights the research gap concerning oligomers.

关键词： oligomers polymers microplastic new pollutants admet

Biological activities of the Ornithogalum orthophyllum and its in silico admet profile

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Traditional Medicine Research 2021年第6期6卷 59-66页

作者： Duygu Taşkın ŞeydaŞentürk Eray Metin Güler Ahmet Doğan Gülden Zehra Omurtag Mizgin Ermanoğlu Turgut Taşkın Department of Analytical Chemistry Hamidiye Faculty of PharmacyUniversity of Health Sciences TurkeyIstanbul 34668Turkey Darıca Leyla Pharmacy Kocaeli 41700Turkey Hamidiye School of Medicine Department of Medical BiochemistryUniversity of Health Sciences TurkeyIstanbul 34668Turkey Department of Pharmaceutical Botany Faculty of PharmacyMarmara UniversityIstanbul 34854Turkey Department of Pharmaceutical Toxicology School of PharmacyIstanbul Medipol UniversityIstanbul 34810Turkey Department of Pharmacognosy Faculty of PharmacyMarmara UniversityIstanbul 34854Turkey

Background:The bulbs and aerial parts of Ornithogalum are used in Turkey both as food and to treat various ailments,and some of its medical applications are well known.However,the biological activities of Ornithogalum orthophyllum have not yet been investigated.The objective of this study was to examine the antioxidant,urease and cholinesterase enzyme inhibition,and cytotoxic activities of different extracts obtained from the bulb and aerial parts of the O.orthophyllum plant.In addition,the absorption,distribution,metabolism,excretion,and toxicity properties of some phenolic compounds in plants were examined in silico.Methods:The antioxidant activity of the extracts obtained from the aerial parts of O.orthophyllum was investigated using the 2,2-diphenyl-1-picrylhydrazyl,2,2-azinobis(3-ethylbenzothiazoline-6-sulphonic acid),ferric reducing antioxidant power,and cupric reducing antioxidant capacity methods.Urease and cholinesterase enzyme inhibition were determined by using the indophenol and Ellman methods,respectively.The cytotoxic activity of the extracts was measured using a test based on the luminometric readings of the adenosine triphosphate levels of the cells.pkCSM,a free online web server(http://structure.***.cam.***.uk/pkcsm)was used to predict the properties of the compounds analyzed.Results:The methanol extract of the aerial parts of O.orthophyllum was observed to have strong antioxidant and acetylcholinesterase enzyme inhibition potential.The petroleum ether extract of the aerial parts showed the highest anti-urease activity.The chloroform extract of the aerial parts exhibited the highest cytotoxic effect against A431 human epidermoid carcinoma cells.The absorption percentages of protocatechuic acid,p-hydroxybenzoic acid,vanillic acid,and p-coumaric acid compounds from the small intestine were between 71.17%and 93.49%,which were quite high.All the compounds were predicted to be unable to penetrate the central nervous system due to their inability to cross the blood-brain barrier.Not all compounds analy

关键词： Ornithogalum orthophyllum antioxidant cytotoxic anticholinesterase anti-urease admet

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钩吻生物碱的admet预测

钩吻生物碱的ADMET预测

Molecular Modeling, Docking and admet of Dimethylthiohydantoin Derivatives for Prostate Cancer Treatment

中国畜牧兽医学会兽医药理毒理学分会第十三次全国会员代表...

作者：齐雪佳左梦婷黄崇银龚梦蝶梁玲玲刘兆颖湖南农业大学动物医学院

目的:钩吻是马钱科胡蔓藤属植物的全草,作为一种传统药用植物,常被用于祛风、攻毒、消肿和止痛。现代药理学研究也表明,钩吻具有镇痛、免疫调节、抗炎、抗焦虑等药理作用。目前,已从钩吻中分离出了生物碱、环烯醚萜、酚酸类、甾体类、... 详细信息

目的:钩吻是马钱科胡蔓藤属植物的全草,作为一种传统药用植物,常被用于祛风、攻毒、消肿和止痛。现代药理学研究也表明,钩吻具有镇痛、免疫调节、抗炎、抗焦虑等药理作用。目前,已从钩吻中分离出了生物碱、环烯醚萜、酚酸类、甾体类、香豆素、木质素类等多种成分,其中吲哚类生物碱不仅是主要的活性成分,同时也是主要的毒性成分。已从钩吻中分离鉴定出120多种生物碱,根据化学骨架结构特点,可分为钩吻定类、钩吻素甲类、钩吻素子类、胡蔓藤乙素类、育亨宾类和蛇根精类六个类别。不同类别生物碱的毒性差异很大,钩吻定类和胡蔓藤乙素类生物碱的毒性最大,使钩吻的开发与应用受到限制。本研究对钩吻生物碱的吸收、分布、代谢、排泄和毒性（admet）性质进行预测,初步评估钩吻生物碱的成药性和安全性,为钩吻的安全开发提供数据支持。材料和方法:利用admetlab 2.0软件,预测钩吻生物碱的admet性质,主要包括理化性质、药代特性和安全性三个方面。结果和讨论:钩吻生物碱都具有较好的水溶性及脂溶性,符合里宾斯基五原则,具有较好的药代动力学性质,肠道吸收水平较高,可透过血脑屏障,可与血浆蛋白结合,并且均被预测为CYP3A4的底物,无肝毒性及皮肤致敏性,具有线粒体毒性和呼吸系统毒性。结合钩吻生物碱的毒性研究及admet预测结果,钩吻素甲毒性较小,具有更低的线粒体毒性,且不具有hERG抑制性,可作为有潜力的药物进一步开发。

关键词：钩吻生物碱 admet 开发

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Journal of Biophysical Chemistry 2015年第4期6卷 91-117页

作者： Khaled Lotfy Physics Department Faculty of Science Sohag University Sohag Egypt University College of Taiyma Tabuk University Tabuk Saudi Arabia

In silico technique was applied to screen potential of 16 compounds of 5,5-dimethylthiohydantoin derivatives as androgen antagonist. The 3D structure of the protein was obtained from PDB database. Docking analysis of the compounds was performed using hex docking. Molecular modeling analysis exhibits relatively low LUMO-HOMO energy gap of the studied molecules, indicating that it would be kinetically stable. None of the compounds violated Lipinski’s parameters, making them potentially promising agents for biological activities. The title compounds exhibited the lowest docking energy of protein-ligand complex. Finally, the results indicate that these compounds are potentially as an androgen antagonist, and expected to be effective in prostate cancer treatment.

关键词： Androgen Receptor Prostate Cancer Molecular Modeling Molecular Docking admet

基于计算机辅助药物设计方法探讨当归活血作用的物质基础和分子机制

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中国中药杂志 2022年第7期47卷 1942-1954页

作者：林佳姚娟张敏李潮新李亚玲邱璐后叶虎刘永琦靳晓杰甘肃中医药大学药学院甘肃兰州730000 西北中藏药协同创新中心甘肃兰州730000 甘肃中医药大学甘肃省高校重大疾病分子医学与中医药防治研究重点实验室甘肃兰州730000 甘肃中医药大学敦煌医学与转化教育部重点实验室甘肃兰州730000

当归具有良好的活血作用,但目前对其发挥“活血”功效的现代科学原理缺乏系统研究,限制了其现代化开发。该研究采用基于结构相似性的靶点反向预测、复杂网络分析、分子对接、结合自由能计算、聚类分析、admet计算等计算机辅助药物设计... 详细信息

当归具有良好的活血作用,但目前对其发挥“活血”功效的现代科学原理缺乏系统研究,限制了其现代化开发。该研究采用基于结构相似性的靶点反向预测、复杂网络分析、分子对接、结合自由能计算、聚类分析、admet计算等计算机辅助药物设计方法结合体外酶活性测定实验系统探讨了当归发挥活血作用的成分及作用机制。靶点反向预测以及复杂网络分析结果显示当归抗凝血的潜在作用靶点有40个。GO(Gene Ontology)和KEGG(Kyoto Encyclopedia of Genes and Genomes)富集分析表明预测靶点可能通过作用于补体与凝血级联信号通路发挥抗凝血作用。其中,凝血级联反应和血栓形成中的关键酶THR(thrombin)和FXa(coagulation factor Xa)是治疗血栓栓塞性疾病的药物靶点。全成分分子对接以及聚类分析显示当归针对FXa具有更好的选择性。结合自由能打分值筛选出8个潜在活性成分进行体外酶活实验,结果显示8个化合物分别对THR和FXa具有不同程度的抑制作用,且对FXa活性的抑制作用比对THR更强。对8个活性化合物进行药效团模型构建,得到药效特征AAHH,其中A为氢键受体,H为疏水中心。admet计算表明8个活性化合物都具有良好的药动学性质,且安全性较高。该研究以靶点反向预测、复杂网络分析、分子对接及结合自由能计算、体外抗凝活性、分子与靶点的空间结合构象、药效团模型构建及admet参数计算为依据,从大数据层面初步阐明了当归活血作用的物质基础及分子机制,并对活性成分进行了药理、毒理计算,首次从全成分计算结合酶活实验揭示了当归对不同凝血蛋白具有明显的选择性和针对性,反映出不同中药的独特功效具有其生物学基础。该研究可为当归的精准用药及其活血成分的现代化开发提供线索。

关键词：当归活血复杂网络分析 THR FXa 计算机辅助药物设计 admet

ACYCLIC DIENE METATHESIS POLYMERIZATION OF TAILOR-MADE MONOMERS TOWARDS SEQUENCE-REGULATED VINYL COPOLYMERS

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Chinese Journal of Polymer Science 2013年第2期31卷 355-362页

作者： Zi-long Li Lei Li Fu-sheng Du 李子臣 Beijing National Laboratory for Molecular Sciences (BNLMS) Key Laboratory of Polymer Chemistry & Physics of Ministry of Education Department of Polymer Science & Engineering College of Chemistry and Molecular EngineeringPeking University

Acyclic diene metathesis polymerization （admet） enables convenient transfer of sequential information of the designed monomers to the corresponding sequence-regulated copolymers. In this study, two structurally symmetric monomers, M1 and M2, were synthesized via atom transfer radical addition （ATRA） of diethyl meso-2,5- dibromohexanedioate with 1,5-hexadiene and 1,7-octadiene, respectively. Thus, sequenced segment of VB-EA-EA-VB （VB and EA represent vinyl bromide and ethyl acrylate, respectively） was incorporated into the admet diene monomers. admet polymerization of these two monomers with Grubbs first generation catalyst （Grubbs-I） was performed in CH2C12 at 40℃ for 5 days under nitrogen purge. Effects of catalyst amount, monomer concentration and methanol precipitation on the Mp and PDI of polymers were investigated by GPC, and the structures of the formed polymers were characterized by NMR. Our results indicate that using 3.0 mol% of Grubbs-I to monomer can afford polymers with high Mp. Moreover, selective precipitation in methanol enables complete removal of low molecular weight components from the crude products. Meanwhile, M2 exhibits higher admet polymerization reactivity than M1 due to its capability of suppressing negative neighboring group effect.

关键词： admet ATRA Sequence-regulated copolymers.