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Structure-based development of potent and selective type-II kinase inhibitors of RIPK1

Acta Pharmaceutica Sinica B 2024年第1期14卷 319-334页

作者： Ying Qin Dekang Li Chunting Qi Huaijiang Xiang Huyan Meng Jingli Liu Shaoqing Zhou Xinyu Gong Ying Li Guifang xu Rui Zu Hang Xie yechun xu Gang xu Zheng Zhang Shi Chen Lifeng Pan Ying Li Li Tan Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 201210China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Chemical Biology Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Institute of Hepatology National Clinical Research Center for Infectious DiseaseShenzhen Third People’s Hospitalthe Second Affiliated HospitalSchool of MedicineSouthern University of Science and TechnologyShenzhen 518112China Department of Burn and Plastic Surgery Shenzhen Institute of Translational MedicineShenzhen University Medical SchoolShenzhen Second People’s Hospitalthe First Affiliated Hospital of Shenzhen UniversityShenzhen 518035China

Receptor-interacting serine/threonine-protein kinase 1(RIPK1)functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases.A number of allosteric RIPK1 inhibitors(RIPK1i)have been developed,and some of them have already advanced into clinical ***,selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to ***,we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical *** also describe the structure-guided lead optimization of a potent,selective,and orally bioavailable RIPK1i,62,which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory ***,62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

关键词： RIPK1 Necroptosis Type-II kinase inhibitors Rational design Lead optimization Structure‒activity relationship Anti-inflammation Preclinical drug discovery

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Potential treatment of COVID-19 by inhibitors of human dihydroorotate dehydrogenase

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Protein & Cell 2020年第10期11卷 699-702页

作者： yechun xu Hualiang Jiang CAS Key Laboratory of Receptor Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Shanghai Institute for Adva need Immuno chemical Studies and School of Life Science and Tech nology Shan ghaiTech UniversityShanghai 201210China

The ongoing pandemic of severe acute respiratory syn・drome coronavirus 2(SARS・CoV・2),referred to as coronavirus disease 2019(COVID-19),has caused over 13 million infections and over 560,000 deaths worldwide(https://***/emergencies/diseases/novel・coron avirus-2019/sit uation-reports),posing a significant threat to globally public health and *** present,no efficacious antiviral drugs and vaccines have been approved for the prophylaxis or treatment of *** efforts have been made to develop drug and vaccine against *** main protease(Mpro,also called 3CLpro)is an attractive drug target among coronaviruses,and several potent inhibitors of the SARS-CoV-23CLpro together with their crystal structures in complex with the protease have been reported(Dai et al.,2020;Jin et al.,2020;Zhang et al.,2020).

关键词： drugs vaccine acute

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基于无线供能和节点间合作的二进制计算卸载方案

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传感技术学报 2024年第6期37卷 1014-1024页

作者：秦娥许方耀徐也淳池凯凯毛科技李卫锋何文秀浙江工业大学计算机科学与技术学院浙江杭州310023 浙江工业大学公共管理学院浙江杭州310023 浙江华通云数据科技有限公司浙江杭州310030 浙江工业大学之江学院浙江绍兴312030

针对性研究了无线供能下的移动边缘计算,其中计算节点能够自主执行计算任务或将其卸载给空闲节点或边缘服务器,以最大化节点的总计算速率(Sum Computing Rate,SCR)。首先,将SCR最大化问题建模为一个非凸问题,考虑到能量因果和任务因果... 详细信息

针对性研究了无线供能下的移动边缘计算,其中计算节点能够自主执行计算任务或将其卸载给空闲节点或边缘服务器,以最大化节点的总计算速率(Sum Computing Rate,SCR)。首先,将SCR最大化问题建模为一个非凸问题,考虑到能量因果和任务因果等约束。接着,提出了一个基于深度强化学习的解决方案,采用深度神经网络输出近似最优的二进制卸载决策。最后,设计了高效算法来解决在给定卸载决策下的子问题。该方案具备在线学习能力,具有快速收敛和低计算复杂度的特点,实现了近似最大SCR。

关键词：移动边缘计算无线供能节点间协作二进制卸载

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Steered molecular dynamics simulations of protein-ligand interactions

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Science China Chemistry 2004年第5期47卷 355-366页

作者： xu yechun SHEN Jianhua LUO Xiaomin SHEN xu CHEN Kaixian JIANG Hualiang Center for Drug Discovery and Design State Key Laboratory of New Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203 China Center for Drug Discovery and Design State Key Laboratory of New Drug Research Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 201203 China

Studies of protein-ligand interactions are helpful to elucidating the mechanisms of ligands, providing clues for rational drug design. The currently developed steered molecular dy- namics (SMD) is a complementary approach to experimental techniques in investigating the biochemical processes occurring at microsecond or second time scale, thus SMD may provide dynamical and kinetic processes of ligand-receptor binding and unbinding, which cannot be ac- cessed by the experimental methods. In this article, the methodology of SMD is described, and the applications of SMD simulations for obtaining dynamic insights into protein-ligand interactions are illustrated through two of our own examples. One is associated with the simulations of bind- ing and unbinding processes between huperzine A and acetylcholinesterase, and the other is concerned with the unbinding process of α-APAfrom HIV-1 reverse transcriptase.

关键词： molecular dynamics simulation, steered molecular dynamics simulation, atomic force microscope, avidin, biotin,huperzine A, acetylcholinesterase, HIV-1 reverse transcriptas, non-nucleoside RT inhibitor.

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广东省兰科植物1新记录属和2新记录种

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热带作物学报 2024年第7期45卷 1367-1370页

作者：金建鹏陈国棣徐晔春谭健俊朱根发杨凤玺广东省园林花卉种质创新综合利用重点实验室/广东省农业科学院环境园艺研究所广东广州510640 阳江市委台港澳工作办公室广东阳江529599

本研究报道了广东省兰科1个新记录属——拟万代兰属(Vandopsis pfitz.),2个新记录种——拟万代兰[***(Lindl.)Pfitz.]和绒兰[Dendrolirium tomentosum(***)],描述了它们的形态、生境分布,并附彩色照片。此次发现扩展了拟万代兰和绒兰的... 详细信息

本研究报道了广东省兰科1个新记录属——拟万代兰属(Vandopsis pfitz.),2个新记录种——拟万代兰[***(Lindl.)Pfitz.]和绒兰[Dendrolirium tomentosum(***)],描述了它们的形态、生境分布,并附彩色照片。此次发现扩展了拟万代兰和绒兰的分布范围,对研究其植物区系具有重要意义。

关键词：拟万代兰属绒兰兰科新记录广东

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Drug discovery and development targeting the life cycle of SARS-CoV-2

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Fundamental Research 2021年第2期1卷 151-165页

作者： Haixia Su yechun xu Hualiang Jiang CAS Key Laboratory of Receptor Research Shanghai Institute of Materia MedicoChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China

A newly emerged coronavirus,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),belongs to the/β-coronavirus family and shows high similarities with SARS-CoV.O n March 11,2020,the World Health Organization(WHO)declared SARS-CoV-2 a global pandemic,and the disease was named the coronavirus disease 2019(COVID-19).The ongoing COVID-19 pandemic has caused over 46 million infections and over one million deaths worldwide,and the numbers are still *** antiviral agents are urgently needed to combat this *** life cycle of SARS-CoV-2 mainly includes the viral attachment,membrane fusion,genomic replication,assembly and budding of ***,drug development against SARS-CoV-2 currently focuses on blocking spike protein binding to ACE2,inhibiting viral membrane fusion with host cells,and preventing the viral replication by targeting 3C-Iike protease,papain-like protease,RNA-dependent R N A polymerase as well as some host-cell *** this review,the advances of drug development in these three major areas are elaborated.

关键词： SARS-CoV-2 COVID-19 Drug development Antibody Inhibitors

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Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2695-2709页

作者： Jiayi Ye Bo Hou Fangmin Chen Shunan Zhang Muya Xiong Tianliang Li yechun xu Zhiai xu Haijun Yu State Key Laboratory of Drug Research&Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China School of Chemistry and Molecular Engineering East China Normal UniversityShanghai 200241China CAS Key Laboratory of Receptor Research and Drug Discovery and Design CenterShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201210China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310013China

Cancer immunotherapy is impaired by the intrinsic and adaptive immune ***,a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms.A disulfide bond-linked bispecific prodrug of NLG919 and JQ1(namely NJ) was synthesized and self-assembled into a prodrug nanoparticle,which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of *** tumor accumulation via passive tumor targeting,the polymeric shell was detached for facilitating intracellular uptake of the bispecific *** was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide ***1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand *** contrast,NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment,which thus restores robust antitumor immune *** therapy(PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor *** combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.

关键词： Immunotherapy Prodrug nanoparticles Immune evasion Immunogenic cell death Tumor microenvironment

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白掌种质资源主要观赏性状的表型多样性分析

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热带作物学报 2024年第2期45卷 269-277页

作者：周熠玮廖飞雄叶远俊刘小飞徐晔春谭健俊刘金梅广东省农业科院环境园艺研究所/广东省园林花卉种质创新综合利用重点实验室/广州市热带盆栽观赏植物工程技术研究中心广东广州510640 华南农业大学林学与风景园林学院广东广州510642

白掌属植物(Spathiphyllum Schott)是天南星科多年生草本植物,是重要的观叶植物。种质资源表型多样性是观赏植物育种与应用的基础。本研究以20份白掌种质资源为材料,对27个重要的观赏性状进行观测,结合变异分析、相关性分析、聚类分析... 详细信息

白掌属植物(Spathiphyllum Schott)是天南星科多年生草本植物,是重要的观叶植物。种质资源表型多样性是观赏植物育种与应用的基础。本研究以20份白掌种质资源为材料,对27个重要的观赏性状进行观测,结合变异分析、相关性分析、聚类分析和主成分分析等多元统计分析方法解析白掌种质资源表型性状的多样性。结果表明:16个数量型性状的变异系数范围为27.2%~69.9%,其中株高、分芽数、叶片数、叶宽、叶柄粗、花序长和小花数变异较大,而株幅和花序粗变异较小。11个描述型性状可以被划分为2~4个等级,香农-维纳指数范围为0.20~1.01,其中叶形的香农-维纳指数最高,而花被片是否分离和花被片颜色的香农-维纳指数最低。对27个性状进行聚类分析发现,当距离为3时可以划分为Group A和Group B两组;Pearson相关分析表明,27个性状两两之间的相关系数范围为-0.72~0.91。在Group A中,性状之间大部分呈显著相关,其中佛焰苞长分别与佛焰苞宽和花序长的相关系数高达0.91,而在Group B中性状大部分相关性不显著。聚类分析和主成分分析表明,20份白掌种质可以分为GroupI和GroupII。GroupI包括阔叶白掌、绿苞白掌、克利夫兰迪、亮叶、皇后、中花和绿巨人共7份种质,主要特征为植株较高大,叶片较大,佛焰苞较大,花序巨大。Group II包括多花绒白掌、天骄、水草、帕里斯、娇小、维客、美酒、泰勒、科丽丝、甜芝、甜糕、碧绿和阳光之梦,主要特征为分芽数和叶片数较多,更加矮化紧凑。该研究结果可为白掌的种质评价和品种培育提供参考。

关键词：白掌种质资源观赏性状表型多样性

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Flavonoids from the roots and rhizomes of Sophora tonkinensis and their in vitro anti-SARS-CoV-2 activity

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Chinese Journal of Natural Medicines 2023年第1期21卷 65-80页

作者： LI Zhuo XIE Hang TANG Chunping FENG Lu KE Changqiang xu yechun SU Haixia YAO Sheng YE Yang School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China State Key Laboratory of Drug Research and Natural Products Chemistry DepartmentShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Pharmacy University of Chinese Academy of SciencesBeijing 100049China Drug Discovery and Design Center CAS Key Laboratory of Receptor ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhouChina

Acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)had caused a global pandemic since 2019,and posed a serious threat to global health *** Chinese medicine(TCM)has played an indispensable role in the battle against the *** components originated from TCMs were found to inhibit the production of SARS-CoV-23C-like protease(3CLpro)and papain-like protease(PLpro),which are two promising therapeutic targets to inhibit *** study describes a systematic investigation of the roots and rhizomes of Sophora tonkinensis,which results in the characterization of 12 new flavonoids,including seven prenylated flavanones(1−7),one prenylated flavonol(8),two prenylated chalcones(9−10),one isoflavanone(11),and one isoflavan dimer(12),together with 43 known compounds(13−55).Their structures including the absolute configurations were elucidated by comprehensive analysis of MS,1D and 2D NMR data,and time-dependent density functional theory electronic circular dichroism(TDDFT ECD)*** 12 and 51 exhibited inhibitory effects against SARS-CoV-23CLpro with IC_(50) values of 34.89 and 19.88μmol·L^(−1),repectively while compounds 9,43 and 47 exhibited inhibitory effects against PLpro with IC_(50) values of 32.67,79.38,and 16.74μmol·L^(−1),respectively.

关键词： Sophora tonkinensis Flavonoid Anti-SARS-CoV-2 activity SARS-CoV-23CLpro SARS-CoV-2 PLpro

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Applying high-performance computing in drug discovery and molecular simulation

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National Science Review 2016年第1期3卷 49-63页

作者： Tingting Liu Dong Lu Hao Zhang Mingyue Zheng Huaiyu Yang yechun xu Cheng Luo Weiliang Zhu Kunqian Yu Hualiang Jiang State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of Sciences

In recent decades, high-performance computing(HPC) technologies and supercomputers in China have significantly advanced, resulting in remarkable achievements. Computational drug discovery and design,which is based on HPC and combines pharmaceutical chemistry and computational biology, has become a critical approach in drug research and development and is financially supported by the Chinese government. This approach has yielded a series of new algorithms in drug design, as well as new software and databases. This review mainly focuses on the application of HPC to the fields of drug discovery and molecular simulation at the Chinese Academy of Sciences, including virtual drug screening, molecular dynamics simulation, and protein folding. In addition, the potential future application of HPC in precision medicine is briefly discussed.

关键词： high-performance computing computational drug discovery and design virtual screening molecular dynamics simulation protein folding

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