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Anticancer drug discovery by targeting cullin neddylation

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Acta Pharmaceutica Sinica B 2020年第5期10卷 746-765页

作者： Qing Yu Yihan Jiang Yi Sun Cancer Institute of the 2nd Affiliated Hospital Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China Division of Radiation and Cancer Biology Department of Radiation OncologyUniversity of MichiganAnn ArborMI 48109.USA

Protein neddylation is a post-translational modification which transfers the ubiquitin-like protein NEDD8 to a lysine residue of the target substrate through a three-step enzymatic *** bestknown substrates of neddylation are cullin family proteins,which are the core component of Cullin-RING E3 ubiquitin ligases(CRLs).Given that cullin neddylation is required for CRL activity,and CRLs control the turn-over of a variety of key signal proteins and are often abnormally activated in cancers,targeting neddylation becomes a promising approach for discovery of novel anti-cancer *** the past decade,we have witnessed significant progress in the field of protein neddylation from preclinical target validation,to drug screening,then to the clinical trials of neddylation *** this review,we first briefly introduced the nature of protein neddylation and the regulation of neddylation cascade,followed by a summary of all reported chemical inhibitors of neddylation *** then discussed the structure-based targeting of protein-protein interaction in neddylation cascade,and finally the available approaches for the discovery of new neddylation *** review will provide a focused,up-to-date and yet comprehensive overview on the discovery effort of neddylation inhibitors.

关键词： Neddylation Anticancer drug discovery Ubiquitin-proteasome system Small molecule inhibitors Virtual screen High-throughput screening

Three-dimensional aspects of formulation excipients in drug discovery:a critical assessment on orphan excipients,matrix effects and drug interactions

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Journal of Pharmaceutical Analysis 2020年第6期10卷 522-531页

作者： Vijayabhaskar Veeravalli Hanumanth Srikanth Cheruvu Pratima Srivastava Lakshmi Mohan Vamsi Madgula Syngene International Limited Biocon ParkSEZBommasandra Industrial Area-Phase-IV Bommasandra-Jigani Link RoadBangalore560099India GVK BIO Pvt Ltd NacharamHyderabadTelangana500076India

Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete *** excipients used in pharmaceutical formulations are orphanized in preclinical drug *** orphan excipients could enhance formulatability of highly lipophilic ***,they are safe in preclinical species when used below the LD50 ***,when the excipients are used in formulating compounds with diverse physico-chemical properties,they pose challenges by modulating study results through their bioanalytical matrix *** invariably present in study samples and not in the calibration curve standards cause over-/under-estimation of ***,the mechanism by which excipients cause matrix effects and strategies to nullify these effects needs to be ***,formulation excipients cause drug interactions by moderating the pathways of drug metabolizing enzymes and drug transport *** it is not possible to get rid of excipient driven interactions,it is always advised to be aware of these interactions and apply the knowledge to draw meaningful conclusions from study *** this review,we will comprehensively discuss a)orphan excipients that have wider applications in preclinical formulations,b)bioanalytical matrix effects and possible approaches to mitigating these effects,and c)excipient driven drug interactions and strategies to alleviate the impacts of drug interactions.

关键词： Formulation excipients Preclinical drug discovery Matrix effects drug interactions Bioanalysis Pharmacokinetics Formulation development

Facing small and biased data dilemma in drug discovery with enhanced federated learning approaches

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Science China(Life Sciences) 2022年第3期65卷 529-539页

作者： Zhaoping Xiong Ziqiang Cheng Xinyuan Lin Chi Xu Xiaohong Liu Dingyan Wang Xiaomin Luo Yong Zhang Hualiang Jiang Nan Qiao Mingyue Zheng Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and TechnologyShanghaiTech UniversityShanghai 200031China 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 School of Information Science and Technology University of Science and Technology of ChinaHefei 230000China Laboratory of Health Intelligence Huawei Technologies Co.LtdShenzhen 518100China

Artificial intelligence(AI)models usually require large amounts of high-quality training data,which is in striking contrast to the situation of small and biased data faced by current drug discovery *** concept of federated learning has been proposed to utilize distributed data from different sources without leaking sensitive information of the *** emerging decentralized machine learning paradigm is expected to dramatically improve the success rate of AI-powered drug ***,we simulated the federated learning process with different property and activity datasets from different sources,among which overlapping molecules with high or low biases exist in the recorded *** the benefit of gaining more data,we also demonstrated that federated training has a regularization effect superior to centralized training on the pooled datasets with high ***,different network architectures for clients and aggregation algorithms for coordinators have been compared on the performance of federated learning,where personalized federated learning shows promising *** work demonstrates the applicability of federated learning in predicting drug-related properties and highlights its promising role in addressing the small and biased data dilemma in drug discovery.

关键词： federated learning drug discovery Fed AMP Non-IID data

The application of sulfur-containing peptides in drug discovery

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Chinese Chemical Letters 2018年第7期29卷 1079-1087页

作者： Jiaoyan Zhao Xuefeng Jiang Shanghai Key Laboratory of Green Chemistry and Chemical Process School of Chemistry and Molecular EngineeringEast China Normal University State Key Laboratory of Elemento-organic Chemistry Nankai University

In recent decades, peptides as potential drugs were more and more explored with the development of non-oral medicine. There into, sulfur-containing peptide is one of the most popular aspects in peptide drugs due to the introduction of sulfur atoms leading unique *** purpose of the present review is to focus on the discovery of various sulfur-containing peptides with particular emphasis on their pharmacological mechanisms. This review is organized according to the structures of the sulfurcontaining peptides.

关键词： Peptides Disulfide Thioether Thiazole drug discovery

Protein targets for structure-based antiMycobacterium tuberculosis drug discovery

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Protein & Cell 2010年第5期1卷 435-442页

作者： Zhiyong Lou Xiaoxue Zhang Laboratory of Structural Biology Tsinghua UniversityBeijing 100084China Higher Education Press Beijing 100029China

Mycobacterium tuberculosis,which belongs to the genus Mycobacterium,is the pathogenic agent for most tuberculosis(TB).As TB remains one of the most rampant infectious diseases,causing morbidity and death with emergence of multi-drug-resistant and extensively-drugresistant forms,it is urgent to identify new drugs with novel targets to ensure future therapeutic *** this regards,the structural genomics of *** provides important information to identify potential targets,perform biochemical assays,determine crystal structures in complex with potential inhibitor(s),reveal the key sites/residues for biological activity,and thus validate drug targets and discover novel *** this review,we will discuss the recent progress on novel targets for structure-based *** drug discovery.

关键词： Mycobacterium tuberculosis crystal structure drug discovery target

COVID-19 therapeutics:Clinical application of repurposed drugs and futuristic strategies for target-based drug discovery

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Genes & Diseases 2023年第4期10卷 1402-1428页

作者： Sunny Kumar Malini Basu Pratyasha Ghosh Uttam Pal Mrinal K.Ghosh Cancer Biology and Inflammatory Disorder Division Council of Scientific and Industrial Research-Indian Institute of Chemical Biology(CSIR-IICB)TRUE CampusCN-6SectoreVSalt LakeKolkata-700091&4Raja S.C.Mullick RoadJadavpurKolkata 700032India Department of Microbiology Dhruba Chand Halder CollegeDakshin BarasatWest Bengal 743372India Department of Economics Bethune CollegeUniversity of CalcuttaKolkata 700006India

Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)causes the compli-cated disease *** are continuously facing huge problems in the treatment of patients,as COVID-19-specific drugs are not available,hence the principle of drug repurpos-ing serves as a one-and-only ***,the repurposing of many drugs is underway;few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical *** in this review,our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs,the potential mechanism of actions,and the current clinical trial status of various drugs which are under repurposing since early *** last,we briefly proposed the probable phar-macological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines.

关键词： Clinical trials COVID-19 drug discovery Pharmacology Repurposing of drugs SARS-CoV-2

The role of SLC12A family of cation-chloride cotransporters and drug discovery methodologies

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Journal of Pharmaceutical Analysis 2023年第12期13卷 1471-1495页

作者： Shiyao Zhang Nur Farah Meor Azlan Sunday Solomon Josiah Jing Zhou Xiaoxia Zhou Lingjun Jie Yanhui Zhang Cuilian Dai Dong Liang Peifeng Li Zhengqiu Li Zhen Wang Yun Wang Ke Ding Yan Wang Jinwei Zhang Xiamen Cardiovascular Hospital of Xiamen University School of MedicineXiamen UniversityXiamenFujian363001China Institute of Biomedical and Clinical Sciences Medical SchoolFaculty of Health and Life SciencesUniversity of ExeterExeterEX44PSUK Department of Neurology Institutes of Brain ScienceState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceInstitute of Biological ScienceZhongshan HospitalFudan UniversityShanghai200032China Aurora discovery Inc. FoshanGuangdong528300China Institute for Translational Medicine Qingdao UniversityQingdaoShandong266021China School of Pharmacy Jinan UniversityGuangzhou510632China State Key Laboratory of Chemical Biology Research Center of Chemical KinomicsShanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai200032China

The solute carrier family 12(SLC12)of cation-chloride cotransporters(CCCs)comprises potassium chloride cotransporters(KCCs,***1,KCC2,KCC3,and KCC4)-mediated Cl^(-)extrusion,and sodium potassium chloride cotransporters(N[K]CCs,NKCC1,NKCC2,and NCC)-mediated Cl^(-)*** CCCs play vital roles in cell volume regulation and ion ***-of-function or loss-of-function of these ion transporters can cause diseases in many *** recent years,there have been considerable advances in our understanding of CCCs'control mechanisms in cell volume regulations,with many techniques developed in studying the functions and activities of *** approaches to directly measure CCC activity involve assays that measure the transport of potassium substitutes through the *** techniques include the ammonium pulse technique,radioactive or nonradioactive rubidium ion uptakeassay,and thallium ion-uptake ***'activity can also be indirectly observed by measuring gaminobutyric acid(GABA)activity with patch-clamp electrophysiology and intracellular chloride concentration with sensitive microelectrodes,radiotracer^(36)Cl^(-),and fluorescent *** techniques include directly looking at kinase regulatory sites phosphorylation,flame photometry,22Nat uptake assay,structural biology,molecular modeling,and high-throughput drug *** review summarizes the role of CCCs in genetic disorders and cell volume regulation,current methods applied in studying CCCs biology,and compounds developed that directly or indirectly target the CCCs for disease treatments.

关键词： Cation-chloride cotransporters Chloride volume regulation Cotransporter assays drug discovery

Applications and prospects of cryo-EM in drug discovery

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Military Medical Research 2023年第6期10卷 848-861页

作者： Kong-Fu Zhu Chuang Yuan Yong-Ming Du Kai-Lei Sun Xiao-Kang Zhang Horst Vogel Xu-Dong Jia Yuan-Zhu Gao Qin-Fen Zhang Da-Ping Wang Hua-Wei Zhang Department of Biomedical Engineering Southern University of Science and TechnologyShenzhen 518055GuangdongChina Department of Biochemistry and Molecular Biology School of Basic Medical SciencesPeking UniversityBeijing 100191China Department of Structural Biology St.Jude Children’s Research HospitalMemphisTN 38105USA Center for Protein Science and Crystallography School of Life SciencesFaculty of ScienceChinese University of Hong KongHong Kong 999077China Interdisciplinary Center for Brain Information the Brain Cognition and Brain Disease InstituteShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055GuangdongChina Faculty of Life and Health Sciences Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055GuangdongChina Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions Shenzhen 518055GuangdongChina Shenzhen Institute of Advanced Technology Chinese Academy of SciencesShenzhen 518055GuangdongChina State Key Lab for Biocontrol School of Life SciencesSun Yat-Sen UniversityGuangzhou 510275China Cryo‑EM Facility Center Southern University of Science and TechnologyShenzhen 518055GuangdongChina Department of Orthopedics Shenzhen Intelligent Orthopaedics and Biomedical Innovation PlatformGuangdong Provincial Research Center for Artifcial Intelligence and Digital Orthopedic TechnologyShenzhen Second People’s HospitalThe First Affiliated Hospital of Shenzhen UniversityShenzhen 518000GuangdongChina Guangdong Provincial Key Laboratory of Advanced Biomaterials Southern University of Science and TechnologyShenzhen 518055GuangdongChina

drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time-and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy(cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence(AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of mediumresolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.

关键词： Cryo-electron microscopy(cryo-EM) drug discovery Structure-based drug design Fragment-based drug discovery Proteolysis targeting chimeras drug repurposing Artificial intelligence(AI)

Genome-wide pan-GPCR cell libraries accelerate drug discovery

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Acta Pharmaceutica Sinica B 2024年第10期14卷 4296-4311页

作者： Hanting Yang Yongfu Wang Wei Liu Taiping He Jiayu Liao Zhongzhi Qian Jinghao Zhao Zhaotong Cong Dan Sun Zhixiang Liu Can Wang Lingping Zhu Shilin Chen School of Pharmacy Chengdu University of Traditional Chinese MedicineChengdu 611137China Institute of Herbgenomics Chengdu University of Traditional Chinese MedicineChengdu 611137China School of Basic Medical Science Chengdu University of Traditional Chinese MedicineChengdu 611137China Department of Bioengineering University of CaliforniaRiversideCA 92521USA The Huaxi-Cal Research Center for Predictive Intervention Medicine West China HospitalSichuan UniversityChengdu 610041China Chinese Pharmacopoeia Commission Beijing 100061China

G protein-coupled receptors(GPCRs)are pivotal in mediating diverse physiological and pathological processes,rendering them promising targets for drug *** account for about 40%of FDA-approved drugs,representing the most successful drug ***,only approximately 15%of the 800 human GPCRs are targeted by market drugs,leaving numerous opportunities for drug discovery among the remaining *** expression systems play crucial roles in the GPCR drug discovery field,including novel target identification,structural and functional characterization,potential ligand screening,signal pathway elucidation,and drug safety ***,we discuss the principles,applications,and limitations of widely used cell expression systems in GPCR-targeted drug discovery,GPCR function investigation,signal pathway characterization,and pharmacological property *** also propose three strategies for constructing genome-wide pan-GPCR cell libraries,which will provide a powerful platform for GPCR ligand screening,and facilitate the study of GPCR mechanisms and drug safety evaluation,ultimately accelerating the process of GPCR-targeted drug discovery.

关键词： G-protein coupled receptors Genome-wide pan-GPCR Transgenic cell library High-throughput screening drug discovery