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Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application

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Acta Pharmaceutica Sinica B 2024年第2期14卷 623-634页

作者： Jiacheng Xiong Rongrong Cui Zhaojun Li Wei Zhang Runze Zhang Zunyun Fu Xiaohong Liu Zhenghao Li Kaixian Chen 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 College of Computer and Information Engineering Dezhou UniversityDezhou 253023China AI Department Suzhou Alphama Biotechnology Co.Ltd.Suzhou 215000China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and TechnologyShanghaiTech UniversityShanghai 200031China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

Aldehyde oxidase(AOX)is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics.AOX-mediated metabolism can result in unexpected outcomes,such as the production of toxic metabolites and high metabolic clearance,which can lead to the clinical failure of novel therapeutic agents.Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability.In this study,we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism.AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction,while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both tasks.AOMP significantly outperformed the benchmark methods in both cross-validation and external testing.Using AOMP,we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability,which were validated through in vitro experiments.Furthermore,for the convenience of the community,we established the first online service for AOX metabolism prediction based on AOMP,which is freely available at https://***.

关键词： Drugmetabolism Aldehyde oxidase Transferlearning Graph neural network kinase inhibitor

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Inhibition of the CDK9-cyclin T1 protein-protein interaction as a new approach against triple-negative breast cancer

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1390-1405页

作者： Sha-Sha Cheng Yuan-Qing Qu Jia Wu Guan-Jun Yang Hao Liu Wanhe Wang Qi Huang Feng Chen Guodong Li Chun-Yuen Wong Vincent Kam Wai Wong Dik-Lung Ma Chung-Hang Leung Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine University of MacaoMacao 999078China Dr.Neher’s Biophysics Laboratory for Innovative Drug Discovery State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacao 999078China State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products Ningbo UniversityKow loon TongHong Kong 999077China Laboratory of Biochemistry and Molecular Biology School of Marine SciencesNingbo UniversityNingbo 315211China Department of Chemistry Hong Kong Baptist UniversityNingbo 315211China Institute of Medical Research Northwestern Polytechnical UniversityXi'an 710072China Department of Chemistry City University of Hong KongHong Kong 999077China Department of Biomedical Sciences Faculty of Health SciencesUniversity of MacaoMacao 999078China

Cyclin-dependent kinase 9(CDK9) activity is correlated with worse outcomes of triplenegative breast cancer(TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction(PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CN ligand and tested their activity against the CDK9cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.

关键词： Metal complex kinase inhibitor Protein-protein interaction Epigenetics Triple-negative breast cancer Metastasis

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Grifolin,secondary metabolite from the mushroom Albatrellus confluens,a potential ERK1/2 kinase inhibitor

Grifolin,secondary metabolite from the mushroom Albatrellus ...

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2008年中国病理生理学会第十一届肿瘤和第十二届免疫专...

作者： Xiang-jian Luo~1 Mao Ye~2 Su-fang Liu~1 Xue-chi Lin~1 Li-li Li~1 Yan-feng Liu~1 Zi-jian Li~1 Ji-kai Liu~(3*) Ya Cao~(1*) ~1 Cancer Research Institute,Xiangya School of Medicine,Central South University,Changsha,Hunan 410078,P.R.China ~2 School of Ophthalmology and Optometry,Wenzhou Medical College,Wenzhou,,Zhejiang 325027,P.R.China ~3 Department of Phytochemistry,Kunming Institute of Botany,Chinese Academy of Sciences,Kunming,Yunnan 650204,P.R.China

＜正＞Grifolin,a secondary metabolite isolated from the fresh fruiting bodies of the mushroom Albatrellus confiuens,has shown various pharmacological and microbiological effects.In this study,we investigated the mechanism of tumor cells proliferation inhibition by grifolin.The findings suggested that grifolin could downregulate the phosphorylation level of ERK1/2 protein as well as its kinase activity and may act as an ERK1/2 kinase inhibitor in some types of human tumors.Because of the important role of the ERK1/2 pathway in cancer biology,the discovery of potent inhibitors of the important enzymes in this pathway is a highly attractive endeavor both scientifically and commercially.

关键词： Grifolin ERK1/2 kinase inhibitor

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Inhibition of protein kinases by anticancer DNA intercalator, 4-butylaminopyrimido[4',5':4,5]thieno(2,3-b)quinoline

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Acta Pharmaceutica Sinica B 2017年第3期7卷 303-310页

作者： HeggoduG.RohitKumar Chethan S.Kumar Hulihalli N.Kiran Kumar Gopal M.Advi Rao Department of Biochemistry Davangere UniversityShivagangotriTholahunaseDavangere 577002India SS Institute of Medical Sciences and Research Centre JnanashankaraDavangere 577005India

Targeting protein kinases(PKs) has been a promising strategy in treating cancer, as PKs are key regulators of cell survival and proliferation. Here in this study, we studied the ability of pyrimido[4',5':4,5]thieno(2,3-b)quinolines(PTQ) to inhibit different PKs by performing computational docking and in vitro screening. Docking studies revealed that 4-butylaminopyrimido[4',5':4,5]thieno(2,3-b)quinoline(BPTQ) has a higher order of interaction with the kinase receptors than other PTQ derivatives.In vitro screening confirms that BPTQ inhibits VEGFR1 and CHK2, with the IC_(50) values of 0.54 and1.70 mmol/L, respectively. Further, cytotoxicity of BPTQ was measured by trypan blue assay. Treatment with BPTQ decreased the proliferation of HL-60 cells with an IC_(50) value of 12 mmol/L and induces apoptosis, as explicated by the fall in the mitochondrial membrane potential, annexin V labeling and increased expression of caspase-3. Taken together, these data suggest that BPTQ possess ability to inhibit PKs and to induce cell death in human promyelocytic leukemia cells.

关键词： DNA intercalator Molecular docking kinase inhibitor Anticancer drugs Apoptosis Chemotherapy

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Identifying Novel Drug Targets by iDTPnd:A Case Study of kinase inhibitors

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Genomics, Proteomics & Bioinformatics 2021年第6期19卷 986-997页

作者： Hammad Naveed Corinna Reglin Thomas Schubert Xin Gao Stefan T.Arold Michael L.Maitland Toyota Technological Institute at Chicago ChicagoIL 60637USA Department of Computer Science National University of Computer and Emerging SciencesIslamabad 44000Pakistan 2bind GmbH D-93053 RegensburgGermany King Abdullah University of Science and Technology(KAUST) Computational Bioscience Research Center(CBRC)ComputerElectrical and Mathematical Sciences and Engineering(CEMSE)DivisionThuwal 23955Saudi Arabia King Abdullah University of Science and Technology(KAUST) Computational Bioscience Research Center(CBRC)Biological and Environmental Sciences and Engineering(BESE)DivisionThuwal 23955Saudi Arabia Inova Center for Personalized Health and Schar Cancer Institute Falls ChurchVA 22042USA University of Virginia Cancer Center AnnandaleVA 22003USA

Current FDA-approved kinase inhibitors cause diverse adverse effects,some of which are due to the me-chanism-independent effects of these drugs.Identifying these mechanism-independent interactions could improve drug safety and support drug repurposing.Here,we develop iDTPnd(integrated Drug Target Predictor with negative dataset),a computational approach for large-scale discovery of novel targets for known drugs.For a given drug,we construct a positive structural signature as well as a negative structural signature that captures the weakly conserved structural features of drug-binding sites.To facilitate assessment of unintended targets,iDTPnd also provides a docking-based interaction score and its statistical significance.We confirm the interactions of sorafenib,imatinib,dasatinib,sunitinib,and pazopanib with their known targets at a sensitivity of 52%and a specificity of 55%.We also validate 10 predicted novel targets by using in vitro experiments.Our results suggest that proteins other than kinases,such as nuclear receptors,cytochrome P450,and MHC class I molecules,can also be physiologically relevant targets of kinase inhibitors.Our method is general and broadly applicable for the identification of protein–small molecule interactions,when sufficient drug–target 3D data are available.The code for constructing the structural signatures is available at https://sfb.***.edu.sa/Documents/iDTP.zip.

关键词： Protein-drug interaction iDTPnd kinase inhibitor Drug-binding site signature Drug repurposing

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BKI1 Regulates Plant Architecture through Coordinated Inhibition of the Brassinosteroid and ERECTA Signaling Pathways in Arabidopsis

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Molecular Plant 2017年第2期10卷 297-308页

作者： Dongxu Wang Cangjing Yang Haijiao Wang Zhihua Wu Jianjun Jiang Jingjing Liu Zhuona He Fang Chang Hong Ma Xuelu Wang State Key Laboratory of Genetic Engineering Department of Genetics School of Life Sciences Fudan University Shanghai 200438 China College of Life Science and Technology Huazhong Agricultural University No 1 Shizishan Street Wuhan Hubei 430070 China Ministry of Education Key Laboratory of Biodiversity Sciences and Ecological Engineering and Institute of Biodiversity Sciences Institute of Plant Biology School of Life Sciences Fudan University Shanghai 200438 China

Hundreds of leucine-rich repeat receptor-like kinases （LRR-RLKs） play indispensable roles in a wide range of plant developmental and physiological processes. The mechanisms controlling LRR-RLKs at a basal and inactive status are essential but rarely studied. BKI1 is the only reported inhibitor of receptor kinases in Arabidopsis, which negatively regulates BRI1 in the brassinosteroid pathway. In this study, we found that BKI1 can also interact with another important LRR-RLK, ERECTA （ER）. Phenotypic analysis showed that BKI1 and ER together regulate plant architecture, including pedicel orientation, which is a newly reported phenotype in the BR- and ER-mediated developmental processes. Gene expression analysis revealed that BKI1 regulates a subset of ER-responsive genes. kinase assays demonstrated that BKI1 inhibits ER kinase activity. In addition, the release of BKI1 inhibition on ER signaling relies largely on BRI1 activation. Our data provide significant insights into the regulation and activation of RLKs and suggest that BKI1 functions as a common suppressor of the BRI1 and ER signaling pathways.

关键词： BKI1 receptor-like kinase ERECTA kinase inhibitor pedicel orientation crosstalk

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Highlights of the 2nd International Symposium on Tribbles and Diseases: tribbles tremble in therapeutics for immunity, metabolism, fundamental cell biology and cancer

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Acta Pharmaceutica Sinica B 2019年第2期9卷 443-454页

作者： Bing Cui Patrick A. Eyers Leonard L. Dobens Nguan Soon Tan Peter D. Mace Wolfgang A. Link Endre Kiss-Toth Karen Keeshan Takuro Nakamura Warren S. Pear Yodit Feseha Jessica Johnston Arkatiz Carracedo Marcel Scheideler Zabran llyas Robert C. Bauer Jorge D. Erusalimsky Dominika Grzesik Juan Salamanca-Viloria Xiaoxi Lv Yishi Jin Ke Li Guillermo Velasco Shuang Shang Jose M. Lizcano Xiaowei Zhang Jichao Zhou Jiaojiao Yu Fang Hua Feng Wang Shanshan Liu Jinmei Yu Zhuowei Hu State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Department of Biochemistry Institute of Integrative Biology University of Liverpool Division of Molecular Biology and Biochemistry School of Biological Sciences University of Missouri-Kansas City School of Biological Sciences Nanyang Technological University Lee Kong Chian School of Medicine Nanyang Technological University Institute of Molecular and Cell Biology KK Women's and Children Hospital Biochemistry Department School of Biomedical Sciences University of Otago Centre for Biomedical Research (CBMR) University of Algarve Campus de Gambelas Department of Biomedical Sciences and Medicine University of Algarve Algarve Biomedical Center (ABC) University of Algarve Campus de Gambelas Department of Infection Immunity and Cardiovascular Disease University of Sheffield Paul O'Gorman Leukaemia Research Centre Institute of Cancer Sciences University of Glasgow Division of Carcinogenesis The Cancer Institute Japanese Foundation for Cancer Research Department of Pathology and Laboratory Medicine Abramson Family Cancer Research Institute Perelman School of Medicine at the University of Pennsylvania Centre de Recherche en Transplantation et Immunologie (ou CRTI) Inserm Université de Nantes Nantes France Institut de Transplantation Urologie Néphrologie (ou ITUN) CIC bioGUNE CIBERONC Ikerbasque Basque Foundation for Science Biochemistry and Molecular Biology Department University of the Basque Country (UPV/EHU) Institute for Diabetes and Cancer IDC Helmholtz Center Munich Joint Heidelberg-IDC Translational Diabetes Program University Hospital Heidelberg Molecular Metabolic Control Medical Faculty Technical University Munich German Center for Diabetes Research (DZD) Division of Cardiology Department of Medicine Columbia University Irving Medical Center School of Sport and Health Sciences Cardiff Metropolitan Universit

The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.

关键词： Tribbles Immunology Metabolism Cell biology kinase inhibitor Tumorigenesis Metastasis TRIB1 TRIB2 TRIB3 Pseudokinase Inflammation Atomic structure Protein quality control Ubiqutin

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Virtual Screening of Selective Multi-Target kinase inhibitors by Combinatorial Support Vector Machines

Virtual Screening of Selective Multi-Target Kinase Inhibitor...

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中国化学会第27届学术年会

作者：陈宇综 Bioinformatics and Drug Design Group Department of Pharmacy Center for Computational Science and Engineering National University of Singapore

＜正＞Multi-target agents have been increasingly explored for enhancing efficacies and reducing counter-target activities and toxicities. Efficient virtual screening （VS） tools for searching selective multi-target a... 详细信息

关键词： kinase inhibitor SVM multi-target agents

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Hand-Foot Syndrome in a Patient with Metastatic Lung Adenocarcinoma Induced by High-Dose Icotinib:a case report and literature review

Hand-Foot Syndrome in a Patient with Metastatic Lung Adenoca...

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首届浙赣两省肿瘤研究交流会

作者： Yulong Zheng Weijia Fang Nong Xu Department of Medical Oncology the First Affiliated HospitalSchool of MedicineZhejiang University

Icotinib is a new oral epidermal growth factor tyrosine kinase inhibitor(EGFR-TKI).The most frequent sideeffects of icotinib include rash and diarrhea.Hand-foot syndrome(HFS) induced by EGFR-TKI is rare.The present study describes,for the first time,HFS induced by high dose icotinib in a 65-year old female with metastatic lung adeno-carcinoma.The patient developed HFS during the first week of icotinib treatment with characteristic clinical presentation.HFS regressed after icotinib dose-reduction was initiated.HFS may occur with icotinib,especially when administered in high doses.

关键词： hand-foot syndrome epidermal growth factor kinase inhibitor adverse drug reactions

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