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Acta Pharmaceutica Sinica B 2024年第8期14卷 3605-3623页

作者： Zehui Tan Ning Guo Zhi Cao Shuyu Liu Jiayu Zhang Deyi Ma Jiahao Zhang Wencai Lv Nan Jiang Linghe Zang Lihui Wang Xin Zhai Key Laboratory of Structure-Based drug design and Discovery Ministry of EducationShenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmacology Shenyang Pharmaceutical UniversityShenyang 110016China

Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung ***,a series of adenosine-containing derivatives were identified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q *** most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation,self-renewal,migration,and invasion of lung cancer cell lines at low micromolar *** cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS *** the H460R231Q OE cell-derived xenograft(CDX)model,37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks(TGI=54.38%),without obvious toxicities.A pharmacokinetic study revealed that 37 possessed tolerable properties(t_(1/2)=1.93±0.91 h,F=97.2%)after intraperitoneal administration in *** study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling ***,analysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the“Induced-fit”allosteric model in favor to the discovery of potent DOT1L candidates.

关键词： DOT1L R231Q mutation Lung cancer Adenosine-containing inhibitors Epigenetics

Intelligent design and construction of novel APN-based theranostic probe driven by advanced computational methods

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Chinese Chemical Letters 2024年第2期35卷 352-357页

作者： Yingli Zhu Jie Qian Kunqian Yu Jing Hou Yeshuo Ma Fei Chen Jie Dong Wenbin Zeng Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410083China National Engineering research Center of Rice and Byproduct Deep Processing School of Food Science and EngineeringCentral South University of Forestry and TechnologyChangsha 410004China State Key Laboratory of drug research Drug Discovery and Design CenterShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Geriatrics Third Xiangya HospitalCentral South UniversityChangsha 410013China

Multifunctional molecules with both optical signal and pharmacological activity play an important role in drug development,disease diagnosis,and basic theoretical *** N(APN),as a representative tumor biomarker with anti-tumor potential,still lacks a high-precision theranostic probe specifically targeting *** this study,a novel quaternity design strategy for APN theranostic probe was *** proposed strategy utilizes advanced machine learning and molecular dynamics simulations,and cleverly employs the strategy of conformation-induced fluorescence recovery to achieve multi-objective optimization and integration of functional *** this strategy,a unique“Off-On”theranostic probe,ABTP-DPTB,was ingeniously constructed to light up APN through fluorescence restoration,relying on conformation-induced effects and solvent *** from the common diagnostic probes,the intelligent design with non-substrated linkage makes ABTP-DPTB for long-term in-situ *** fabricated probe was used for detecting and inhibiting APN in various environments,with a better in vitro inhibitory than golden-standard drug bestatin.

关键词： Theranostic probe Artificial intelligence Conformational restriction Fluorescence restoration design strategy

Artificial-intelligent-powered safety and efficiency improvement for controlling and scheduling in integrated railway systems

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High-speed Railway 2024年第3期2卷 172-179页

作者： Liu J. Liu G. Wang Y. Zhang W. Beijing National Railway research & design Institute of Signal & Communication group Co. Ltd Beijing 100070 China Engineering research Center of Railway Industry of Intelligent and Autonomous Train Control Beijing 100070 China

The multi-mode integrated railway system, anchored by the high-speed railway, caters to the diverse travel requirements both within and between cities, offering safe, comfortable, punctual, and eco-friendly transportation services. With the expansion of the railway networks, enhancing the efficiency and safety of the comprehensive system has become a crucial issue in the advanced development of railway transportation. In light of the prevailing application of artificial intelligence technologies within railway systems, this study leverages large model technology characterized by robust learning capabilities, efficient associative abilities, and linkage analysis to propose an Artificial-intelligent (AI)-powered railway control and dispatching system. This system is elaborately designed with four core functions, including global optimum unattended dispatching, synergetic transportation in multiple modes, high-speed automatic control, and precise maintenance decision and execution. The deployment pathway and essential tasks of the system are further delineated, alongside the challenges and obstacles encountered. The AI-powered system promises a significant enhancement in the operational efficiency and safety of the composite railway system, ensuring a more effective alignment between transportation services and passenger demands. © 2024 Beijing Jiaotong University

关键词： Artificial intelligence High-speed railway Large-scale mode, system framework Multi-mode railway system Safety and efficiency improvement

In silico off-target profiling for enhanced drug safety assessment

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2927-2941页

作者： Jin Liu Yike Gui Jingxin Rao Jingjing Sun Gang Wang Qun Ren Ning Qu Buying Niu Zhiyi Chene Xia Sheng Yitian Wang Mingyue Zheng Xutong Li College of Pharmaceutical Sciences Zhejiang UniversityHangzhou 310058China drug Discovery and design Center State Key Laboratory of Drug ResearchShanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Nanjing University of Chinese Medicine Nanjing 210023China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyHangzhou 330106China

Ensuring drug safety in the early stages of drug development is crucial to avoid costly failures in subsequent ***,the economic burden associated with detecting drug off-targets and potential side effects through in vitro safety screening and animal testing is *** off-target interactions,along with the adverse drug reactions they induce,are significant factors affecting drug *** assess the liability of candidate drugs,we developed an artificial intelligence model for the precise prediction of compound off-target interactions,leveraging multi-task graph neural *** outcomes of off-target predictions can serve as representations for compounds,enabling the differentiation of drugs under various ATC codes and the classification of compound ***,the predicted off-target profiles are employed in adverse drug reaction(ADR)enrichment analysis,facilitating the inference of potential ADRs for a *** the withdrawn drug Pergolide as an example,we elucidate the mechanisms underlying ADRs at the target level,contributing to the exploration of the potential clinical relevance of newly predicted off-target ***,our work facilitates the early assessment of compound safety/toxicity based on off-target identification,deduces potential ADRs of drugs,and ultimately promotes the secure development of drugs.

关键词： drug safety Off-target prediction Adverse drug reactions Toxicity Molecular representation Artificial intelligence

Efficacy and safety of Y- 2 sublingual tablet for patients with acute ischaemic stroke: protocol of a phase III randomised double- blind placebo- controlled multicentre trial

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Stroke & Vascular Neurology 2024年第1期9卷 90-95页

作者： Yu Fu Renhong Tang Rong Chen Anxin Wang Jinsheng Ren Shunwei Zhu Xiaofei Feng Dongsheng Fan Deparment of Neurology Peking University Third HospitalBeijingChina State Key Laboratory of Neurology and Oncology drug development NanjingJiangsuChina Simcere Pharmaceutical group Limited NanjingJiangsuChina Neurodawn Pharmaceutical Co. LtdNanjingJiangsuChina Department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina China National Clinical research Center for Neurological Diseases Beijing Tiantan HospitalCapital Medical UniversityBeijingChina

Background and purpose Clinical studies have demonstrated that edaravone dexborneol can improve the functional outcomes in patients with acute ischaemic stroke(AIS).The present clinical trial aimed at testing the efficacy and safety of Y-2 sublingual tablet on 90-day functional outcome in patients with *** and design This is a randomised,double-blind,placebo-controlled,multicentre,parallel-group trial of Y-2 sublingual tablet on patients with *** estimated 914 patients at age of 18–80 years with AIS within 48 hours after symptom onset from 40 hospitals will be randomly assigned to receive Y-2 sublingual tablet or placebo for 14 *** are at score 6–20 points on National Institutes of Health Stroke Scale(NIHSS)and had a modified Rankin Scale(mRS)≤1 before this stroke,except mechanical thrombectomy and neuroprotective agents *** outcomes The primary outcome is the proportion of patients with mRS≤1 on day 90 after *** efficacy outcomes include mRS score on day 90,the proportion of patients with mRS≤2 on day 90;the change of NIHSS score from baseline to day 14 and the proportion of patients with NIHSS score≤1 at the days 14,30 and *** This trial will provide valuable evidence for the efficacy and safety of Y-2 sublingual table for improving 90 days the functional outcomes in patients with *** registration number NCT04950920.

关键词： patients protective centre

αExtractor: a system for automatic extraction of chemical information from biomedical literature

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Science China(Life Sciences) 2024年第3期67卷 618-621页

作者： Jiacheng Xiong Xiaohong Liu Zhaojun Li Hongzhong Xiao Guangchao Wang Zhenjiang Niu Chaoyuan Fei Feisheng Zhong Gang Wang Wei Zhang Zunyun Fu Zhiguo Liu Kaixian Chen Hualiang Jiang Mingyue Zheng drug Discovery and design Center State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China AI Department Suzhou Alphama Biotechnology Co.Ltd.Suzhou 215125China College of Computer and Information Engineering Dezhou UniversityDezhou 253023China

Dear Editor,Great progress has been made using artificial intelligence(AI) techniques in learning knowledge from biomedical databases in recent years, revolutionizing the study of many fields, such as protein structure prediction and protein design(Madani et al., 2023). However, there is massive biomedical knowledge not curated in the form of structured data but hidden in primary scientific literature.

关键词： has such knowledge

design,synthesis and biological evaluation of fluorescent derivatives of ursolic acid in living cells

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Chinese Chemical Letters 2024年第5期35卷 287-289页

作者： Wenyi Mei Lijuan Xie Xiaodong Zhang Cunjian Shi Fengzhi Wang Qiqi Fu Zhenjiang Zhao Honglin Li Yufang Xu Zhuo Chen Shanghai Key Laboratory of New drug design State Key Laboratory of Bioreactor EngineeringSchool of PharmacyEast China University of Science and TechnologyShanghai 200237China Innovation Center for AI and drug Discovery East China Normal UniversityShanghai 200062China Lingang Laboratory Shanghai 200031China

Ursolic acid(UA)is a naturally occurring ursane triterpenoid,which exhibits a wide range of unique biological *** clarify its mechanism of action(MOA),a series of fluorescent derivatives of UA(5a-c)were designed and synthesized by conjugation with 7-nitrobenzo-2-oxa-1,3-diazole(NBD)*** them,5c exhibited similar anti-proliferative activity with UA against HCT116 cells(half maximal inhibitory concentration(IC_(50))=9.21±0.50μmol/L).Cell imaging experiment indicated that 5c was rapidly taken up in HCT116 cells in a dose and time-dependent ***,5c was found to localize in endoplasmic reticulum(ER),lysosomes,and mitochondria,but not in nucleus of HCT116 cells by confocal microscopy *** MOA proved that UA induced autophagy with a unique intracellular distribution mechanism involving ER and *** all,our work provides new clues for revealing the molecular mechanism of UA as an antitumor agent.

关键词： Pentacyclic triterpenoid Ursolic acid Fluorescent derivatives Autophagy Apoptosis

Biological factors driving colorectal cancer metastasis

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World Journal of Gastrointestinal Oncology 2024年第2期16卷 259-272页

作者： Shuai-Xing An Zhao-Jin Yu Chen Fu Min-Jie Wei Long-Hai Shen Department of Pharmacology School of PharmacyChina Medical UniversityShenyang 110122Liaoning ProvinceChina Liaoning Key Laboratory of Molecular Targeted Antitumor drug development and Evaluation Liaoning Cancer Immune Peptide Drug Engineering Technology Research CenterKey Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors(China Medical University)Ministry of EducationShenyang 110122Liaoning ProvinceChina BD Department Greenpine Pharma Group Co.LtdTianjin 300020China Center of Oncology Genertec Liaoyou Gem Flower HospitalPanJin 124010Liaoning ProvinceChina

Approximately 20%of colorectal cancer(CRC)patients present with metastasis at *** Stage I-III CRC patients who undergo surgical resection,18%typically suffer from distal metastasis within the first three years following initial *** median survival duration after the diagnosis of metastatic CRC(mCRC)is only 9 *** is traditionally considered to be an advanced stage malignancy or is thought to be caused by incomplete resection of tumor tissue,allowing cancer cells to spread from primary to distant organs;however,increa-sing evidence suggests that the mCRC process can begin early in tumor *** patients present with high heterogeneity and diverse cancer phenotypes that are classified on the basis of molecular and morphological *** genomic and nongenomic events can induce subclone diversity,which leads to cancer and *** the course of mCRC,metastatic cascades are associated with invasive cancer cell migration through the circulatory system,extravasation,distal seeding,dormancy,and reactivation,with each step requiring specific molecular ***,cancer cells presenting neoantigens can be recognized and eliminated by the immune *** this review,we explain the biological factors that drive CRC metastasis,namely,genomic instability,epigenetic instability,the metastatic cascade,the cancer-immunity cycle,and external lifestyle *** remarkable progress in CRC research,the role of molecular classification in therapeutic intervention remains *** review shows the driving factors of mCRC which may help in identifying potential candidate biomarkers that can improve the diagnosis and early detection of mCRC cases.

关键词： cancer Metastasis cascade Cancer immunity Genomic variation Epigenetic instability Lifestyle factor

The dark side of cyclooctatetraene(COT):Photophysics in the singlet states of“self-healing”dyes

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Chinese Chemical Letters 2024年第8期35卷 225-228页

作者： Supphachok Chanmungkalakul Syed Ali Abbas Abedi Federico J.Hernández Jianwei Xu Xiaogang Liu Fluorescence research group Singapore University of Technology and DesignSingapore 487372Singapore Department of Chemistry University College LondonLondon WC1H 0AJUnited Kingdom Institute of Sustainability for Chemicals Energy and Environment(ISCE2)Agency for ScienceTechnology and Research(A^(∗)STAR)Jurong Island 627833Singapore

Cyclooctatetraene(COT)attachment to fluorophores(“self-healing”dyes)is known for quenching reac-tive triplet states via triplet-state energy transfer(TET),enhancing ***,COT’s impact on singlet states remains *** calculations reveal that COT induces energy transfer to dark states in deep blue dyes while promoting photoinduced electron transfer(PET)and intersystem crossing(ISC)in visible dyes,potentially compromising brightness and/or *** address this,we pro-pose the use of △E descriptor to optimize COT’s *** findings uncover COT’s multifaceted *** insights will guide the development of superior triplet state quenchers and photostable dyes.

关键词： Cyclooctatetraene Photostability Triplet state quencher Energy transfer Electron transfer

research on Electromagnetic Wave Absorption Based on Electrospinning Technology

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Chinese Journal of Chemistry 2024年第7期42卷 777-789页

作者： Baoding Li Jing Qiao Yue Liu Haoyuan Tian Wei Liu Qilei Wu Zhou Wang Jiurong Liu Zhihui Zeng Key Laboratoryfor Liquid-Solid StructuralEvolution and Processing of Materials Schoolof Materials Science and EngineeringShandong UniversityJinanShandong 250061China China North Industries group 53rd research Institute JinanShandong 250000China School of Mechanical Engineering Shandong UniversityJinanShandong 250061China Institute of Crystal Materials State Key Laboratory of Crystal MaterialsShandong UniversityJinanShandong 250100China Shenzhen research Institute of Shandong University ShenzhenGuangdong 518057China Science and Technology on Electromagnetic Compatibility Laboratory China Ship Development and Design CentreWuhanHubei 430064China suzhou research Institute of Shandong University SuzhouJiangsu215123China

At present,in order to overcome electromagnetic interference and prevent electromagnetic harm,the research of new and efficient electromagnetic wave absorbing materials has become the research focus in the field of materials *** one-dimensional structure can promote the impedance matching and attenuation characteristics of the absorbing ***,as an effective method to prepare nanofibers with high length-diameter ratio,has been widely concerned because it is suitable for struc-tural design of various *** this paper,the research progress and absorption properties of nano-fiber materials prepared by electrospinning combined with different processes are introduced.

关键词： Electromagnetic wave(EMW)absorbing Electrospinning Nanofiber Impedance matching Nanocomposite