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AI enhances drug discovery and development

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National Science Review 2024年第3期11卷 52-54页

作者： Fang Bai Shiliang Li Honglin Li Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University Lingang Laboratory Innovation Center for AI and Drug discovery East China Normal University

The advent of the third wave of artificial intelligence(AI) heralds a new era in drug discovery. AI-powered techniques can be characteristic of identifying features that are difficult for humans to interpret from big ...

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Lithium polysulfide solvation and speciation in the aprotic lithium-sulfur batteries

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Particuology 2024年第6期89卷 238-245页

作者： Jinhao Zhang Qingshan Fu Peng Li Ruibo Linghu Xiaozhong Fan Haibin Lin Juncao Bian Songbai Han Gengzhi Sun Long Kong Frontiers Science Center for flexible Electronics and Xi’an Institute of flexible Electronics Northwestern Polytechnical UniversityXi’an710129China China Automotive Innovation Corporation Nanjing211100China Academy for Advanced Interdisciplinary Studies Southern University of Science and TechnologyShenzhen518055China Institute of Advanced Materials Nanjing Tech UniversityNanjing211816China

Fingerprinting sulfur speciation in aprotic electrolytes is a key to understand fundamental chemistry and design well-performing lithium–sulfur(Li–S)*** polysulfide(LiPS)dissolution and deposition in ether-based electrolytes during redox reactions have been probed and established by spectroscopy and ***,detailed LiPS structure and solvation properties influenced by conventional and newly developed electrolytes remain elusive,which exert fundamental challenges and practical difficulties in decoupling battery performance from electrolyte *** perspective aims to provide timely information to uncover underlying mechanisms that rein in sulfur speciation by considering the charge density of LiPSs and the coordination strength of solvents/*** discussion starts with unlocking the baseline electrolyte formulation to investigate its role in LiPS formation and *** that,the term coordination strength is used instead of donor number and dielectric constant to describe interactions between solvents and LiPSs and to reveal LiPS structure *** work is expected to encourage the discovery of new electrolyte working mechanisms to develop energy-dense and power-intensive Li–S batteries.

关键词： Sulfur speciation Redox kinetics Coordination strength Solvation chemistry Lithium-sulfur batteries

discovery of first-in-class DOT1L inhibitors against the R231Q gain-of-function mutation in the catalytic domain with therapeutic potential of lung cancer

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3605-3623页

作者： Zehui Tan Ning Guo Zhi Cao Shuyu Liu Jiayu Zhang Deyi Ma Jiahao Zhang Wencai Lv Nan Jiang Linghe Zang Lihui Wang Xin Zhai Key Laboratory of Structure-Based Drug Design and discovery Ministry of EducationShenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmacology Shenyang Pharmaceutical UniversityShenyang 110016China

Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung ***,a series of adenosine-containing derivatives were identified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q *** most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation,self-renewal,migration,and invasion of lung cancer cell lines at low micromolar *** cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS *** the H460R231Q OE cell-derived xenograft(CDX)model,37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks(TGI=54.38%),without obvious toxicities.A pharmacokinetic study revealed that 37 possessed tolerable properties(t_(1/2)=1.93±0.91 h,F=97.2%)after intraperitoneal administration in *** study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling ***,analysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the“Induced-fit”allosteric model in favor to the discovery of potent DOT1L candidates.

关键词： DOT1L R231Q mutation Lung cancer Adenosine-containing inhibitors Epigenetics

Highly Aromatic Norditerpenoid Heterodimers and Monomers from Trigonostemon fragilis

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Engineering 2024年第7期38卷 144-154页

作者： Jun-Su Zhou Long Cheng Yuan Gao Zhan-Peng Ge Bin Zhou Jing-Ya Li Jin-Xin Zhao Jian-Min Yue State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Shandong Laboratory of Yantai Drug discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantai 264117China

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(-)-4 are 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(-)-8 and(+)-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)lmol·L^(-1),as active as the positive control BMS-303141,and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.

关键词： Norditerpenoid heterodimer Trigonostemon fragilis Euphorbiaceae Trigofragiloid Structural revision Adenosine triphosphate-citrate lyase(ACLY) inhibitory activity

Dual PPAR delta/gamma agonist offer therapeutic potential for Alzheimer's disease

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Neural Regeneration Research 2024年第6期19卷 1175-1176页

作者： Ian Steinke Meenakshi Singh Rajesh Amin Department of Drug discovery and Development Auburn UniversityAuburn AlabamaALUSA

The increasing incidence of Alzheimer's disease(AD)in the aging population,indicates the critical need for the development of novel targeted molecular therapies for ameliorating AD ***,clinical and preclinical evidence demonstrates that peroxisomal proliferator activating receptors(PPAR)agonists regulate energy and lipid homeostasis in models of diabetes,as well as improve spatial memory in animal models of AD(Khan et al.,2019).

关键词： Alzheimer clinical homeostasis

Directly targeting BAX for drug discovery:Therapeutic opportunities and challenges

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2378-2401页

作者： Zhenwei Zhang Linghui Hou Dan Liu Shenglin Luan Min Huang Linxiang Zhao Key Laboratory of Structure-Based Drugs Design&discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China China Resources Sanjiu Medical&Pharmaceutical Co. Ltd.Shenzhen 518000China

For over two decades,the development of B-cell lymphoma-2(Bcl-2)family therapeutics has primarily focused on anti-apoptotic proteins,resulting in the first-in-class drugs called BH3 mimetics,especially for Bcl-2 inhibitor *** pro-apoptotic protein Bcl-2-associated X protein(BAX)plays a crucial role as the executioner protein of the mitochondrial regulated cell death,contributing to organismal development,tissue homeostasis,and *** dysregulation of BAX is closely associated with the onset and progression of diseases characterized by pathologic cell survival or death,such as cancer,neurodegeneration,and heart *** addition to conducting thorough investigations into the physiological modulation of BAX,research on the regulatory mechanisms of small molecules identified through biochemical screening approaches has prompted the identification of functional and potentially druggable binding sites on BAX,as well as diverse all-molecule BAX *** review presents recent advancements in elucidating the physiological and pharmacological modulation of BAX and in identifying potentially druggable binding sites on ***,it highlights the structural and mechanistic insights into small-molecule modulators targeting diverse binding surfaces or conformations of BAX,offering a promising avenue for developing next-generation apoptosis modulators to treat a wide range of diseases associated with dysregulated cell death by directly targeting BAX.

关键词： Apoptosis Pro-apoptotic protein BAX Dynamic conformational activation Small-molecule apoptosis modulators

Sigmatropic rearrangements of B(MIDA)-propargylic alcohols towards the diverse synthesis of α-functionalized organoborons

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Science China Chemistry 2024年第2期67卷 568-575页

作者： Jiasheng Qian Li-Cai Liu Zhi-Hao Chen Yuan Liu Yin Li Qingjiang Li Honggen Wang Guangdong Key Laboratory of Chiral Molecule and Drug discovery School of Pharmaceutical SciencesSun Yat-Sen UniversityGuangzhou510006China

α-Functionalized organoborons are useful building blocks and key structural elements in functional *** previous synthesis relied on the famous Matteson reaction or the late-stage borylative modification of alkynes or ***,the synthetic transformation of borylated building blocks offers another useful strategy and is currently actively *** report herein that B(MIDA)-propargylic alcohols(BPAs) are a useful type of borylated building *** two complementary functional group handles(alkyne and hydroxyl) in close proximity,the redox-neutral [3,3] and [2,3] sigmatropic rearrangements of BPAs allow the efficient synthesis of several types of α-functionalized boronates,including α,β-unsaturated acylborons,α-S/P-substituted allenylborons,boryl-substituted thiazoles and a borylated α,β-unsaturated hydrazine,some of which are otherwise challenging targets using other synthetic methods.

关键词： organoboron diverse synthesis sigmatropic rearrangement heteroarene amide

Nuance of inward rectifying potassium(Kir)channel dysfunctions in neurodegenerative diseases

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Neural Regeneration Research 2024年第6期19卷 1195-1196页

作者： Benjamin Garland Linlin Ma Griffith Institute for Drug discovery&School of Environment and Science Griffith UniversityNathanBrisbaneQLDAustralia

Neurodegenerative disorders are highly prevalent and diverse in *** manifestation largely depends on the cell types involved,with aberrant inflammatory episodes progressively inducing a constellation of phenotypes that are classified into specific diseases based on their neuropathological *** two most prevalent neurodegenerative diseases worldwide,Alzheimer’s disease(AD)and Parkinson’s disease(PD),for example,share notable similarities,yet they differ in terms of the specific cell types lost within the central nervous system(CNS).The significant and progressive loss of cortical and certain subcortical neurons in various regions is a major defining trait of *** contrast,the specific loss of dopaminergic neurons(DA)within the substantial nigra pars compacta(SNpc)is sufficient to cause motor symptoms associated with *** devastating condition arising from neurodegeneration within the CNS,amyotrophic lateral sclerosis(ALS),results in the progressive death of upper and lower motor *** degeneration originates in oligodendrocytes,whose defective myelination abilities lead to the denervation of the anterior horn,aggravating motor neuron death.

关键词： diseases degenerative degeneration

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