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Pharmacophore modeling for the identification of small-molecule inhibitors of TACE

中国药理学与毒理学杂志 2015年第S1期29卷 95-96页

作者： Li-juanLIU Ka-HoLEUNG ShengLIN DanielShiu-HinCHAN DewiSUSANTI Wei-dongRAO PhilipWaiHongCHAN Dik-LungMA Chung-HangLEUNG State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao Macao China Department of Chemistry Hong Kong Baptist University Hongkong China Division of Chemistry and Biological Chemistry School of Physical and Mathematical Sciences Nanyang Technological University Singapore 637371 Singapore School of Chemistry Monash University Ciayton 3800 Victoria Australiate

OBJECTIVE To employ pharmacophore modeling to identify a TACE inhibitor from an inhouse database of 66 organic compounds.METHODS To identify the common features required for TACE inhibition,we generated a pharmacophore model from a set of TACE-selective inhibitor using the Common Feature Pharmacophore Model protocol implemented in Discovery Studio 3.1.1.A fluorimetric assay was used to investigate the potential ability of compounds to inhibit TACE enzymatic activity.The ability of compound 1 to inhibit TACE activity in a human monocyte THP-1 cell line was evaluated by ELISA.RESULTS In this study,apharmacophore model constructed from a training set of TACE inhibitors was used to screen an in-house database of organic compounds,from which compound 1 emerged as a top candidate.In a cell-free assay,compound 1inhibited TACE enzymatic activity in a dose-dependent manner.Moreover,compound 1 inhibited the production of soluble TNF-αin human acute monocytic leukemia THP-1 cells without impacting nitric oxide production,and exhibited anti-proliferative activity against THP-1cells.CONCLUSION Compound 1 was found to inhibit TACE enzymatic activity in a cell-free system and LPS-induced TNF-αsecretion in cellulo.We envisage that compound 1 may be employed as a useful scaffold for the development of more potent TACE inhibitors.

关键词： pharmacophore TACE tumor necrosis factor virtual s

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Virtual screening and optimization of typeⅡ inhibitors of JAK2 from a natural product library

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中国药理学与毒理学杂志 2015年第S1期29卷 98-99页

作者： Dik-LungMA DanielShiu-HinCHAN GuoWEI Hai-jingZHONG HuiYANG LaiToLEUNG ElizabethA.GULLEN PaulineChIU Yung-ChiCHENG Chung-hangLEUNG Department of Chemistry Hong Kong Baptist University Hong Kong China Department of Chemistry and the State Key Laboratory of Synthetic Chemistry University of Hong Kong Hong Kong China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao Macao China Department of Pharmacology Yale University School of Medicine New Haven CT 06520 USA

OBJECTIVE To utilize a structure-based lead optimization approach to generate novel natural product-like typeⅡ inhibitors of JAK2 using the DOLPHIN protocol.METHODS Initially,the DOLHPIN computational protocol was employed to convert an active(DFG-in)conformation of JAK2 into a typeⅡ-compatible conformation,which was used as a model for the structure-based virtual screening of 150 000 natural product-like compounds in silico.The novel biflavonoid analogues were designed and synthesized based on the structure of lead compound and then tested for JAK2 and STAT3 inhibitory activity,cytotoxicity and HCV antiviral activity.RESULTS The top eleven highest-scoring compounds were generated from the initial high-throughput virtual screening.Amentoflavone 1a,a biflavonoid from the Chinese plant Gingko biloba,emerged as a promising candidate for further biological evaluation.In dose-response experiments,amentoflavone 1ainhibited JAK2 activity in a concentration dependent fashion with an IC50 value of 5μmol·L-1.As a proof-of-concept,we designed nine analogues 1b-1j with the addition of one or more aliphatic side chains to the biflavonoid scaffold of 1a.The octyl(C8)analogue 1bdisplayed superior potency against JAK2 activity and HCV activity compared to the parent compound 1a,validating the structure-based lead optimization approach used in this study.Moreover,kinetic analysis indicated that analogue 1bexhibited a non-competitive mode of inhibition,suggesting that this compound may be a putative typeⅡ inhibitor of JAK2.CONCLUSION Amentoflavone 1ahas been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library.In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo.Molecular modeling and kinetic experiments suggested that the analogues may function as typeⅡ inhibitors of JAK2.

关键词： JAK2 natural products virtual screening structure-

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Identification of a natural product-like STAT3 dimerization inhibitor by structure-based virtual screening

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中国药理学与毒理学杂志 2015年第S1期29卷 95-95页

作者： Li-juanLIU Ka-HoLEUNG DanielShiu-HinCHAN Dik-LungMA Chung-HangLEUNG State Key Laboratory of Quality Research in Chinese Medicine University of Macao Macao SAR China Department of Chemistry Hong Kong Baptist University Kowloon Tong Hong Kong China

OBJECTIVE To apply molecular docking techniques to identify STAT3 inhibitors from a database of over 90 000 natural product and natural product-like compounds.METHODS Molecular docking was used for the virtual screening campaign and hit validation of STAT3 inhibitor.To further evaluate the potency of candidates at inhibiting STAT3-DNA binding activity,a STAT3 and STAT1transcription factor ELISA was performed.A dual-luciferase reporter assay,co-immunoprecipitation assay and Western blotting were carried out for the investigation of effect of compound 1 on STAT3-driven transcription,STAT3 dimerization and STAT3 phosphorylation.Finally,the cell toxicity of compound 1 was assessed by using MTT assay on different cell lines.RESULTS The virtual screening campaign furnished fourteen hit compounds,from which compound 1 emerged as a top candidate.Compound 1inhibited STAT3DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with selectivity over STAT1 and comparable potency to the wellknown STAT3 inhibitor S3I-201.Furthermore,compound 1 inhibited STAT3 dimerization and decreased STAT3 phosphorylation in cells without affecting STAT1 dimerization and phosphorylation.Compound 1 also exhibited selective anti-proliferative activity against cancer cells over normal cells in vitro.CONCLUSION The benzofuran derivative 1 was identified as a potential inhibitor of STAT3 dimerization using in silico screening.Molecular docking analysis suggested that compound 1 might putatively function as an inhibitor of STAT3 dimerization by binding to the SH2 domain.To the best of our knowledge,compound 1 has not been reported as a STAT3 inhibitor and no biological activity of compound 1 has been presented in the literature.

关键词： STAT3 natural products virtual screening dimerizat

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Special Topic:DNA-Based Biosensors

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Journal of Analysis and Testing 2022年第1期6卷 1-2页

作者： Jue-Wen Liu dik-Lung Ma Department of Chemistry University of WaterlooWaterlooON N2L 3G1Canada Department of Chemistry Hong Kong Baptist UniversityKowloon TongHong Kong 999077China

While the function of DNA in biology is for storage of genetic information,chemists have developed methods to obtain DNA sequences with catalytic and molecular recognition functions.Thus,DNA is a highly attractive molecule for developing biosensors.DNA probes are known for their detection of complementary DNA and RNA.In addition,DNA aptamers allow for the detection of,essentially,any type of molecule.By coupling DNA with biological elements such as CRISPR-Cas12,highly sensitive detection with signal amplification can also be achieved.Overall,using DNA as a sensor component and as a target are hot areas of research for biomedical diagnosis,environmental monitoring,and food safety.

关键词： diagnosis attractive complementary

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Discovery of a tetrahydroisoquinoline-based CDK9-cyclin T1 proteineprotein interaction inhibitor as an anti-proliferative and anti-migration agent against triple-negative breast cancer cells

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Genes & Diseases 2022年第6期9卷 1674-1688页

作者： Shasha Cheng Guan-Jun Yang Wanhe Wang dik-Lung Ma Chung-Hang Leung State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoTaipaMacao SARPR China Department of Chemistry Hong Kong Baptist UniversityKowloon TongHong Kong SARPR China Institute of Medical Research Northwestern Polytechnical UniversityXi’anShaanxi 710072PR China Department of Biomedical Sciences Faculty of Health SciencesUniversity of MacaoMacao SARPR China

Triple-negative breast cancer(TNBC)is a highly aggressive and metastasizing cancer that has the worst prognosis out of all breast cancer subtypes.The epithelial emesenchymal transition(EMT)and cancer stem cells(CSCs)have been proposed as important mechanisms underlying TNBC metastasis.CDK9 is highly expressed in breast cancer,including TNBC,where it promotes EMT and induces cancer cell stemness.In this study,we have identified a tetrahydroisoquinoline derivative(compound 1)as a potent and selective CDK9-cyclin T1 inhibitor via virtual screening.Interestingly,by targeting the ATP binding site,compound 1 not only inhibited CDK9 activity but also disrupted the CDK9-cyclin T1 proteineprotein interaction(PPI).Mechanistically,compound 1 reversed EMT and reduced the ratio of CSCs by blocking the CDK9-cyclin T1 interaction,leading to reduced TNBC cell proliferation and migration.To date,compound 1 is the first reported tetrahydroisoquinoline-based CDK9-cyclin T1 ATP-competitive inhibitor that also interferes with the interaction between CDK9 and cyclin T1.Compound 1 may serve as a promising scaffold for developing more selective and potent anti-TNBC agents.Our work also provides insight into the role of the CDK9-cyclin T1 PPI on EMT and CSCs and highlights the feasibility and significance of targeting CDK9 for the treatment of TNBC.

关键词： Cancer stem cells CDK9-cyclin T1 Epithelial mesenchymal transition Proteineprotein interaction(PPI) Triple-negative breast cancer(TNBC)

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The roles of atypical protein kinase Cs(aPKCs) in the nervous system: targets for neuroregeneration?

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Neural Regeneration Research 2020年第8期15卷 1475-1476页

作者： Dennis dik-Long Chau Kwok-Fai Lau School of Life Sciences The Chinese University of Hong Kong

The protein kinase C(PKC)family:PKC family is a subgroup of the AGC serine-threonine kinases that consists of 10 distinct members in mammals(Spitaler and Cantrell,2004).They all contain a C-terminal catalytic domain that is connected to the N-terminal regulatory domains.PKCs are subdivided into three classes according to their structures and activators.The classical/conventional PKC isoforms possess tandem C1 domains that bind to their well-known activators diacylglycerol and phorbol esters and also contain a C2 domain that mediates the binding of Ca^2+-sensitive anionic phospholipids.

关键词： domains. subgroup system

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Development of an orally bioavailable selective inhibitor of the menin-MLL

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Genes & Diseases 2023年第5期10卷 1735-1738页

作者： Hai-Jing Zhong Wanhe Wang Wei Zhou Jia-Xin Liang Yung-Chi Cheng dik-Lung Ma Chung-Hang Leung State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao SARChina Department of Chemistry Hong Kong Baptist UniversityKowloon TongHong Kong SARChina Department of Pharmacology Yale University School of MedicineNew HavenCT 06520USA Department of Biomedical Sciences Faculty of Health SciencesUniversity of MacaoMacao SARChina International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education(MOE) College of PharmacyJinan UniversityGuangzhouGuangdong 510632China

The protein–protein interaction between menin and mixed lineage leukemia(MLL)plays an important role in the development of human hepatocellular carcinogenesis(HCC)and is associated with poor prognosis of HCC patients.1,2 Hence,interrupting the menin-MLL interaction is an attractive strategy in cancer treatment,particularly for liver cancer.3,4 In this study,we identified complex C1 as the first rhodium(III)-based orally bioavailable selective inhibitor of the menin-MLL interaction for HCC.

关键词： MLL prognosis carcinogenesis

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Group 8–9 Metal‑Based Luminescent Chemosensors for Protein Biomarker Detection

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Journal of Analysis and Testing 2018年第1期2卷 77-89页

作者： dik‐Lung Ma Chun Wu Guodong Li Chung‐Hang Leung Department of Chemistry Faculty of ScienceHong Kong Baptist UniversityKowloon TongHong KongChina State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacaoChina

The development of transition metal complex-based luminescent chemosensors has recently aroused increasing interest for protein biomarker labelling and detection,especially for the real-time diagnosis and treatment of disease.This is owing to their unique photophysical properties,particularly their long-lived and environmentally sensitive emission,which can be easily controlled via the structural modification of ligands.In this overview,we highlight recent examples of protein biomarker detection using group 8–9 metal-based luminescent chemosensors,including the frequently employed ruthenium(II)and iridium(III)complexes.Various mechanisms and sensing modes are described and compared,and the outlook and future directions of this field are discussed as well.

关键词： Chemosensor Biomarker Metal complex Luminescence

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FE65:a hub for neurodevelopment

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Neural Regeneration Research 2024年第9期19卷 1883-1884页

作者： Yuqi Zhai Laura Lok-Haang Ng Dennis dik-Long Chau Kwok-Fai Lau School of Life Sciences Faculty of ScienceThe Chinese University of Hong KongHong Kong Special Administrative RegionChina

FE65,initially identified as a binding partner of amyloid precursor protein(APP),is an adaptor protein enriched in the brain and regulated during development.FE65 belongs to the FE65 protein family.This family is comp... 详细信息

关键词： family development partner

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Recent advances in the managements of type 2 diabetes mellitus and natural hypoglycemic substances

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Food Science and Human Wellness 2022年第5期11卷 1121-1133页

作者： Chong Ning Yuhan Jiao Jiaqi Wang Weiwei Li Jingqiu Zhou Yi-Chieh Lee dik-Lung Ma Chung-Hang Leung Rugang Zhu Hui-Min David Wang College of Light Industry Liaoning UniversityShenyang 110036China Department of Life Sciences National Chung Hsing UniversityTaichung 402TaiwanChina Department of Chemistry Hong Kong Baptist UniversityKowloon Tong 999077Hong KongChina State Key Laboratoryof Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao 999078China Graduate Institute of Biomedical Engineering National Chung Hsing UniversityTaichung 402TaiwanChina Graduate Institute of Medicine College of MedicineKaohsiung Medical UniversityKaohsiung City 807TaiwanChina Department of Medical Laboratory Science and Biotechnology China Medical UniversityTaichung City 404TaiwanChina

Diabetes has become a global concern at present,among which type 2 diabetes mellitus(T2DM)accounts for approximately 90%-95%of patients.T2DM is a type of metabolic disorder syndrome that results from a genetic defect,and it is based on insulin resistance and an insulin secretion disorder.The occurrence of T2DM is usually the outcome of both genetic and environmental factors and their interactions.The etiology and pathogenesis of diabetes have not been fully elucidated,and no radical therapeutic cure has been found.Patients with T2DM suffer from complications such as the development of a chronic hyperglycemic condition and even serious metabolic disorders and organ damage in the body and depression and dementia,in addition to other chronic complications.Many studies have suggested that diet is crucial in the development of diabetes and the control of blood glucose.Natural substances have the characteristics of low toxicity and few side effects and may be key to the development of diabetic health products and preventive treatments.This paper reviews the etiology,pathogenesis,risks,treatments and diets related to T2DM to summarize the types of recently available natural products,from both local and foreign sources,for lowering blood glucose at home and their application in supplementary hypoglycemic foods.The key findings and conclusions suggest that there are various known T2DM-inducing factors,including genetic and environmental factors and three types of hybrid factors.

关键词： Obesity Type 2 diabetes mellitus Etiological agent Diet Insulin resistance Natural substances

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