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Rapid discovery of two unprecedented meroterpenoids from Daphne altaica *** molecular networking integrated with MolNetEnhancer and Network Annotation Propagation

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Chinese Chemical Letters 2024年第8期35卷 294-298页

作者： Wei-Yu Zhou Zi-Han Xi Ning-Ning Du Li Ye Ming-Hao Jiang Jin-Le Hao Bin Lin Guo-Dong Yao Xiao-Xiao Huang Shao-Jiang Song Key Laboratory of Computational Chemistry-Based Natural Antitumor drug Research&Development Liaoning ProvinceEngineering Research Center of Natural Medicine Active Molecule Research&DevelopmentLiaoning ProvinceKey Laboratory of Natural Bioactive Compounds Discovery&ModificationShenyangSchool of Traditional Chinese Materia Medic1Shenyang Pharmaceutical UniversityShenyang 110016China Key Laboratory of Structure-Based drug Design and discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China

Under the guidance of the approach which integrates molecular networking,MolNetEnhancer and Net-work Annotation Propagation(NAP),daphnaltaicanoids A and B(1 and 2)with unprecedented 9-oxa-tetracyclo[6.***.1.0^(2,6).0^(8,13)]pentadecane and tetracyclo[5.***.0.1^(2,5).2^(4,11)]tridecane central frameworks were iso-lated from Daphne altaica Pall.,representing two types of unparalleled meroterpenoid *** struc-tures were elucidated by extensive spectroscopic analysis,nuclear magnetic resonance(NMR)calcula-tions,DP4+analysis and electronic circular dichroism(ECD)*** plausible biosynthetic path-ways for 1 and 2 were ***,2 exerted potent neuroprotective activities which were su-perior to trolox at 12.5 and 25μmol/***,1 and 2 exhibited more noticeable acetylcholinesterase inhibitory activities than *** docking simulations were performed to explore the inter-molecular interaction of compounds 1 and 2 with *** bioactivity evaluation results highlight the prospects of 1 and 2 as a novel category of neurological agents.

关键词： Daphne altaica Pall. Molecular networking MolNetEnhancer NAP Unprecedented meroterpenoid frameworks Neuroprotective activities Acetylcholinesterase inhibitors

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Anti-inflammatory germacrane-type sesquiterpene lactones from Vernonia sylvatica

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Chinese Journal of Natural Medicines 2024年第6期22卷 568-576页

作者： WANG Min LI Han HU Bintao TANG Chunping XU Hui KE Changqiang XIE Zuoquan YE Yang YAO Sheng State Key Laboratory of drug Research&Natural Products Research Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China School of Life Science and Technology Shanghai Tech UniversityShanghai 201210China State Key Laboratory of drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Zhongshan Institute for drug discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshan 528400China

Nine new germacranolides,sylvaticalides A−H(1-9),and three known analogues(10-12)were isolated from the aeri-al part of Vernonia *** structures were established using comprehensive spectroscopic analysis,including high-resolution electrospray ionization mass spectroscopy(HR-ESI-MS)and 1D and 2D nuclear magnetic resonance(NMR)*** absolute configurations were determined by X-ray diffraction *** anti-inflammatory activities of all isolated compounds were as-sessed by evaluating their inhibitory effects on the nuclear factor kappa B(NF-κB)pathway,which was activated by lipopolysacchar-ide(LPS)-stimulated human THP1-Dual cells,and the interferon-stimulated gene(ISG)pathway,activated by STING agonist MSA-2 in the same cell *** 1,2 and 6 showed inhibitory effects on the NF-κB and ISG signaling pathways,with IC_(50)values ranging from 4.12 to 10.57μmol·L^(−1).

关键词： Vernonia sylvatica Germacrane-type sesquiterpene lactone Sylvaticalides A−H Anti-inflammatory NF-κB path-way ISG pathway

A proteomic landscape of pharmacologic perturbations for functional relevance

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Journal of Pharmaceutical Analysis 2024年第1期14卷 128-139页

作者： Zhiwei Liu Shangwen Jiang Bingbing Hao Shuyu Xie Yingluo Liu Yuqi Huang Heng Xu Cheng Luo Min Huang Minjia Tan Jun-Yu Xu State Key Laboratory of drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing210023China Zhongshan Institute for drug discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdong528400China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing210023China

Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.

关键词： Proteomics drug Perturbation drug target drug combination

A lateral-immobilization zebrafish microfluidic chip-based system for in vivo real-time evaluation of antithrombotic agents

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Chinese Chemical Letters 2024年第3期35卷 312-315页

作者： Lijuan He Hongxia Du Yi Yang Zhihua Guan Jinjin Li Honglin Li Xudong Lin Lili Zhu Shanghai Key Laboratory of New drug Design School of PharmacyEast China University of Science&TechnologyShanghai 200237China Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument School of Biomedical EngineeringShenzhen Campus of Sun Yat-sen UniversityShenzhen 518000China Innovation Center for AI and drug discovery East China Normal UniversityShanghai 200062China

Thrombosis remains a major global health concern mainly characterized by high rates of morbidity and *** models serve as an indispensable tool to understand the underlying pathogenesis of thrombosis and assess the efficacy of novel antithrombotic ***,zebrafish has emerged as a valuable model organism for thrombosis ***,the traditional method of studying zebrafish thrombosis requires a laborious and time-consuming procedure,including anesthesia and manual immobilization of *** this study,based on hydrodynamic force,a lateral-immobilization zebrafish microfluidic chip(LIZMC)was designed to evaluate the cardiovascular system of multiple larvae within a single microscope field of ***,coupling with microscope imaging,real-time monitoring of the peripheral blood circulation in the tail of phenylhydrazine(PHZ)-induced zebrafish thrombosis was ***,the reliability of LIZMC for in vivo evaluation of antithrombotic agents in zebrafish was verified using ***,this novel LIZMC-based system can be used for in vivo zebrafish thrombosis studies and rapid screening of antithrombotic agents.

关键词： Microfluidic chip Zebrafish Thrombosis In vivo evaluation Real-time monitor

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CA IX-targeted Ag_(2)S quantum dots bioprobe for NIR-II imaging-guided hypoxia tumor chemo-photothermal therapy

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Journal of Pharmaceutical Analysis 2024年第6期14卷 878-888页

作者： Xinyue Cui Zhuang Hu Ruihan Li Peng Jiang Yongchang Wei Zilin Chen Department of Radiation and Medical Oncology Zhongnan Hospital of Wuhan University and School of Pharmaceutical SciencesWuhan UniversityWuhan430071China Key Laboratory of Combinatorial Biosynthesis and drug discovery Ministry of EducationHubei Province Engineering and Technology Research Center for Fluorinated PharmaceuticalsWuhan430071China

Hypoxia is the common characteristic of almost all solid tumors,which prevents therapeutic drugs from reaching the ***,the development of new targeted agents for the accurate diagnosis of hypoxia tumors is widely *** carbonic anhydrase IX(CA IX)is abundantly distributed on the hypoxia tumor cells,it is considered as a potential tumor biomarker.4-(2-Aminoethyl)benzenesulfonamide(ABS)as a CA IX inhibitor has inherent inhibitory activity and good targeting *** this study,Ag_(2)S quantum dots(QDs)were used as the carrier to prepare a novel diagnostic and therapeutic bioprobe(Ag_(2)S@polyethylene glycol(PEG)-ABS)through ligand exchange and amide condensation ***_(2)S@PEG-ABS can selectively target tumors by surface-modified ABS and achieve accurate tumor imaging by the near infrared-II(NIR-II)fluorescence characteristics of Ag_(2)S *** modification of Ag_(2)S QDs greatly improves its water solubility and stability,and therefore achieves high photothermal stability and high photothermal conversion efficiency(PCE)of 45.17%.Under laser irradiation,Ag_(2)S@PEG-ABS has powerful photothermal and inherent antitumor combinations on colon cancer cells(CT-26)in *** also has been proved that Ag_(2)S@PEG-ABS can realize the effective treatment of hypoxia tumors in vivo and show good ***,it is a new efficient integrated platform for the diagnosis and treatment of hypoxia tumors.

关键词： CA IX-targeted Hypoxia tumor combination therapy NIR-II imaging Photothermal effect

Transient receptor potential channels and calcium dysregulation: a pathogenic duo in Parkinson's disease

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Neural Regeneration Research 2025年第3期20卷 808-810页

作者： Iqira Saeed Linlin Ma Griffith Institute for drug discovery Griffith UniversityNathanBrisbaneQLDAustralia School of Environment and Science Griffith University NathanBrisbaneQLDAustralia

Parkinson's disease(PD) has a complex and multifactorial pathophysiology. Various studies, conducted both in pre-clinical models and PD patients, have reported a link between the disruption of calcium(Ca^(2+)) homeostasis and the subsequent development of PD. Ca^(2+) regulation is crucial for neuronal survival, differentiation,exocytosis at synapses,gene transcription,and proliferation.

关键词： homeostasis clinical subsequent

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黄花三宝木中高度芳香化的降二萜异源二聚体及其单体（英文）

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Engineering 2024年第7期 144-154页

作者：周均愫成龙高源葛战鹏周彬李静雅赵金鑫岳建民 State Key Laboratory of drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shandong Laboratory of Yantai drug discovery Bohai Rim Advanced Research Institute for Drug Discovery

Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A–C(denoted as compounds 1–3) and (+)-and (—)-trigofragiloid D (compound 4)-and three new phenanthrenone norditerpenoids-namely,trigofragiloids E–G (compounds 5–7)-were isolated from Trigonostemon *** 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid;they have been identified as class 2 atropisomers by means of quantum chemical *** 3 is an unprecedented phenylpropanoid–norditerpenoid adduct with a new dimerization *** (+)-and (—)-4are the first example of S-shaped 1,4-dioxane-fused norditerpenoid *** by the structure elucidation of compound 4,two co-occurring analogues,actephilol A and epiactephilol A,were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers,(+)-and (—)-8and (+)-and (—)-9,*** structures were characterized using a combined ***,compound 7 exhibits remarkable adenosine triphosphate-citrate lyase (ACLY) inhibition with a halfmaximal inhibition concentration (IC50) value of (0.46±0.11)μmol·L—1,as active as the positive control BMS-303141,and a molecular docking study offers deep insight into the interaction between compound7 and ACLY.

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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

Emerging Novel Therapeutic Approaches for the Treatment of Alzheimer’s Disease

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Advances in Alzheimer's Disease 2024年第3期13卷 65-94页

作者： Amit Panwar Mohd. Imran Khan Rajesh Kumar Rakesh Kumar Santosh Kumar Rai Anil Kumar New drug discovery Research Mankind Research Centre Mankind Pharma Limited Gurugram India

Alzheimer’s disease (AD) is caused by synaptic failure and the excessive accumulation of misfolded proteins especially A β and tau, and associated with memory loss and cognitive impairment. Treatment of AD mainly consists of symptomatic therapy and disease-modifying therapy (DMT). Several monotherapies including small molecules or antibodies have been evaluated through multiple clinical trials, but a very few have been approved by the USFDA to intervene the disease’s pathogenesis. Past research has shown multifactorial nature of AD, therefore, multi-target drugs were proposed to target different pathways at the same time, however, currently no rationally designed multi-target directed ligand (MTDL) has been clinically approved. Different combinations and bispecific antibodies are also under development. Novel approaches like stem cell-based therapies, microRNAs, peptides, ADCs and vaccines cast a new hope for AD treatment, however, a number of questions remained to be answered prior to their safe and effective clinical translation. This review explores the small molecules, MTDL, and antibodies (monospecific and bispecific) for the treatment of AD. Finally, future perspectives (stem cell therapy, PROTAC approaches, microRNAs, ADC, peptides and vaccines) are also discussed with regard to their clinical applications and feasibility.

关键词： Alzheimer’s Disease (AD) Disease-Modifying Therapy (DMT) MicroRNAs PROTAC