ACS Medicinal Chemistry Letters最新文献_第3页

The Water-Soluble [60]Fullerene Derivatives as Binders of SARS-CoV-2 Proteins 水溶性[60]富勒烯衍生物作为SARS-CoV-2蛋白结合物的研究

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-08-03 DOI: 10.1021/acsmedchemlett.6c00282

Katarzyna Malarz, Tainah Dorina Marforio, Robert Gawecki, Dominik Dreszer, Matteo Calvaresi, Maciej Serda

{"title":"The Water-Soluble [60]Fullerene Derivatives as Binders of SARS-CoV-2 Proteins","authors":"Katarzyna Malarz, Tainah Dorina Marforio, Robert Gawecki, Dominik Dreszer, Matteo Calvaresi, Maciej Serda","doi":"10.1021/acsmedchemlett.6c00282","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00282","url":null,"abstract":"Water-soluble fullerene derivatives represent emergingmolecularnanomaterials for antiviral drug discovery, yet their target selectivityagainst SARS-CoV-2 proteins remains insufficiently defined. Here,four functionalized [60]fullerenes, C60(OH)24, C60ser, C60ALA, and C60Trp, wereevaluated as binders of key SARS-CoV-2 targets involved in viral entryand replication: spike glycoprotein, papain-like protease, 3CL mainprotease, and RNA-dependent RNA polymerase. Microscale thermophoresisrevealed distinct target-dependent binding profiles governed by fullerenefunctionalization. The C60Trp fullerene was the most activederivative, binding Spike with nanomolar affinity (Kd =94.8 nM) and showing micromolar affinity toward papain-like proteaseand 3CL main protease. Docking and molecular dynamics simulationssupported the preferential interaction of C60Trp with thespike protein cavity through combined fullerene cage complementarityand polar interactions with lysine and arginine residues. The testedderivatives showed low cytotoxicity in A549 cells, and C60Trp was efficiently internalized. These findings identify tryptophan-functionalized[60]fullerene as a promising multivalent scaffold for SARS-CoV-2 proteintargeting.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2153–2159"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Structure-Guided Development of Selective HDAC4 and HDAC7 Inhibitors That Modulate Th17 Cell Transcription 调控Th17细胞转录的选择性HDAC4和HDAC7抑制剂的结构导向开发

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-16 DOI: 10.1021/acsmedchemlett.6c00328

Bharath Kumar Gajjela, Nilesh Zaware, Anbalagan Jaganathan, Jamel Meslamani, Alannah LeJeune, Jyoti Singh, Roberto Sanchez, Ka Lung Cheung, Ming-Ming Zhou

{"title":"Structure-Guided Development of Selective HDAC4 and HDAC7 Inhibitors That Modulate Th17 Cell Transcription","authors":"Bharath Kumar Gajjela, Nilesh Zaware, Anbalagan Jaganathan, Jamel Meslamani, Alannah LeJeune, Jyoti Singh, Roberto Sanchez, Ka Lung Cheung, Ming-Ming Zhou","doi":"10.1021/acsmedchemlett.6c00328","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00328","url":null,"abstract":"Class IIa histonedeacetylases (HDACs) are attractive therapeutictargets due to their specialized regulatory functions and restrictedexpression patterns. Recent studies identified HDAC4 and HDAC7 ascritical regulators of Th17-cell differentiation, acting through distincttranscriptional mechanisms to promote Th17 lineage commitment. Buildingon these findings, we designed, synthesized, and characterized a seriesof selective HDAC4/7 inhibitors derived from the Class IIa scaffoldTMP269. Structure-guided optimization of the metal-proximal and hydrophobic-bindingregions generated analogs with improved potency and enhanced isoformselectivity. Luciferase-based transcriptional assays, protein-bindingstudies, and molecular docking analyses revealed distinct structure–activityrelationships that govern HDAC4 versus HDAC7 selectivity. Severalcompounds exhibited potent and selective inhibition of HDAC4- or HDAC7-dependenttranscriptional activity, providing valuable chemical probes to dissectthe individual functions of these enzymes in Th17 biology. These next-generationinhibitors establish a foundation for developing targeted therapiesfor Th17-driven inflammatory disorders, including inflammatory boweldisease.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2206–2210"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Fragment Optimization─Simple SMILES String Manipulation Strategies to Optimize a Hit or Fragment 片段优化─简单的SMILES字符串操作策略来优化命中或片段

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-22 DOI: 10.1021/acsmedchemlett.6c00181

Kevin P. Cusack, Jake M. Aquilina

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Structure-Based Drug Design of Quinoline CYP8B1 Inhibitors for the Potential Treatment of Metabolic Disease 基于结构的喹啉类CYP8B1抑制剂治疗代谢性疾病的药物设计

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-16 DOI: 10.1021/acsmedchemlett.6c00387

Amy Bittner McCracken, Derun Li, John P. Caldwell, Claire Lankin, Jayaram Tagat, Tanweer Khan, Ashwin Rao, Tianyuan Zhang, Mary Ann Caplen, Andreas Verras, Peter Orth, Alan Hruza, Thu Ho, Samantha Allen, Nathaniel L. Elsen, Karen Dingley, Ruth Duffy, Thomas Wisniewski, Bethann Murphy, Jose Castro-Perez, Kenny Wong, Eric Streckfuss, Jinchu Liu, Weidong Tong, Brian McKittrick

{"title":"Structure-Based Drug Design of Quinoline CYP8B1 Inhibitors for the Potential Treatment of Metabolic Disease","authors":"Amy Bittner McCracken, Derun Li, John P. Caldwell, Claire Lankin, Jayaram Tagat, Tanweer Khan, Ashwin Rao, Tianyuan Zhang, Mary Ann Caplen, Andreas Verras, Peter Orth, Alan Hruza, Thu Ho, Samantha Allen, Nathaniel L. Elsen, Karen Dingley, Ruth Duffy, Thomas Wisniewski, Bethann Murphy, Jose Castro-Perez, Kenny Wong, Eric Streckfuss, Jinchu Liu, Weidong Tong, Brian McKittrick","doi":"10.1021/acsmedchemlett.6c00387","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00387","url":null,"abstract":"CYP8B1 has been identified as a potential target forthe treatmentof metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD)and type 2 diabetes (T2D). CYP8B1 enzyme inhibitor 1 wasdiscovered from a high-throughput screen of our compound collection;however, its poor metabolic stability prevented further in vivo evaluation.Leveraging structure-based drug design, metabolite identificationand metabolic stability-guided DMPK optimization, and library synthesisto rapidly expand SAR, we identified compound 9 withsubstantially improved DMPK properties. Compound 9 showedrobust in vivo CYP8B1 inhibition in mice and provided the foundationfor further optimization of this class of CYP8B1 inhibitors.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2245–2250"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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The Preparation and Systematic Evaluation of Ligated Ni(II) Pre-Catalysts (NiPC) in Common Single Electron Cross-Coupling Reactions 常见单电子交叉耦合反应中Ni（II）预催化剂（NiPC）的制备及系统评价

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-16 DOI: 10.1021/acsmedchemlett.6c00332

Jeeyoung Park, Andre Sanchez, Chi “Chip” Le, Yaroslav Boyko, Samantha A. Burgess, Melissa Tan, Michael Ardolino, Lee Robison, Justin A. Newman, Brandon A. Vara

{"title":"The Preparation and Systematic Evaluation of Ligated Ni(II) Pre-Catalysts (NiPC) in Common Single Electron Cross-Coupling Reactions","authors":"Jeeyoung Park, Andre Sanchez, Chi “Chip” Le, Yaroslav Boyko, Samantha A. Burgess, Melissa Tan, Michael Ardolino, Lee Robison, Justin A. Newman, Brandon A. Vara","doi":"10.1021/acsmedchemlett.6c00332","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00332","url":null,"abstract":"The advent of single-electron, nickel-mediated cross-couplingreactionshas fundamentally transformed how carbon bonds can be forged and isnow a mainstay of modern synthesis and medicinal chemistry. Nickelis a prevailing transition metal that facilitates these innovations,and yet despite its obvious competence, standardized practices regardingNi/ligand preparation and administration, as separate entities oras a single precomplex or catalyst, have not been systematically established.This study investigates the synthesis, isolation, and efficacy ofsimple, ligated Ni(II) precatalysts (NiPCs) to expedite and standardizeprotocols for contemporary single-electron nickel-mediated cross-couplingreactions. We demonstrate the effectiveness of a library of isolatedNiPCs in commonly used singleton transformations and high-throughputexperimentation (HTE) setups with broad application to pharmaceuticalchemistry. By illuminating the practical rules that govern NiPC synthesisand administration, this work equips the community with an actionableunderstanding to enable wide, normalized adoption of simple NiPC methods.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2230–2237"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Antibody Hotspot-Centric de Novo Design of Peptide Inhibitors of Influenza A Virus Membrane Fusion 以抗体热点为中心的甲型流感病毒膜融合肽抑制剂的从头设计

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-21 DOI: 10.1021/acsmedchemlett.6c00321

Rameshwar U. Kadam, Jarek Juraszek, Davide Branduardi, Jeroen van Ameijde, Divita Garg, Jan Vermond, Mandy Jongeneelen, Chan Tang, Ronald Vogels, Maria J. P. van Dongen, Boerries Brandenburg, Robert H. E. Friesen, Ian A. Wilson

{"title":"Antibody Hotspot-Centric de Novo Design of Peptide Inhibitors of Influenza A Virus Membrane Fusion","authors":"Rameshwar U. Kadam, Jarek Juraszek, Davide Branduardi, Jeroen van Ameijde, Divita Garg, Jan Vermond, Mandy Jongeneelen, Chan Tang, Ronald Vogels, Maria J. P. van Dongen, Boerries Brandenburg, Robert H. E. Friesen, Ian A. Wilson","doi":"10.1021/acsmedchemlett.6c00321","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00321","url":null,"abstract":"Here we report the applicability of a hotspot-centricapproachfor de novo computational design of l-peptidesbased on crystal structures of antigen–antibody complexes.Broadly neutralizing antibodies (bnAbs) FI6v3 and CR9114, which targetinfluenza A virus hemagglutinin (HA), guided the peptide design. Disembodiedhotspot residues from these bnAbs were selected and anchored ontoknown peptide scaffolds (≤35 amino acids) from the ProteinData Bank (PDB). The top-scoring designs were subsequently synthesized,folded, tested in vitro, and structurally characterizedin complex with HA. The designed peptides demonstrate structural andfunctional mimicry by recapitulating the binding mode of the bnAbson HA and act as inhibitors of low-pH-dependent conformational transitionsin HA that facilitate membrane fusion. These findings demonstratethat hotspot-guided design strategy, previously applied to proteinsand d-peptides, can be effectively extended to l-peptide scaffolds, enabling the development of functional HA inhibitorsinformed by key residues at antigen–antibody interfaces.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 10","pages":"2191–2196"},"PeriodicalIF":3.9,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Novel Treatment of Irritable Bowel Syndrome (IBS) and Other Disorders of the Peripheral Nervous System Using Peripherally Restricted Positive Allosteric Modulators of GABA-A Receptor 利用GABA-A受体外周限制性正变构调节剂治疗肠易激综合征（IBS）和其他外周神经系统疾病的新方法

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-07 DOI: 10.1021/acsmedchemlett.6c00467

Ahmed F. Abdel-Magid

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A-iMPO: A Design-Time Prediction Toolbox for Blood Brain Barrier Permeation Using an Integrated and Interpretable Multiparameter Optimization Framework A- impo：设计时血脑屏障渗透预测工具箱，使用集成和可解释的多参数优化框架

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-27 DOI: 10.1021/acsmedchemlett.6c00347

Samiron Phukan, Ashis Nandy, Manjunath Ramarao

{"title":"A-iMPO: A Design-Time Prediction Toolbox for Blood Brain Barrier Permeation Using an Integrated and Interpretable Multiparameter Optimization Framework","authors":"Samiron Phukan, Ashis Nandy, Manjunath Ramarao","doi":"10.1021/acsmedchemlett.6c00347","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00347","url":null,"abstract":"Designtime prioritization of central nervous system(CNS) drugcandidates remains a challenge due to the restrictive nature of theblood–brain barrier (BBB) governing brain exposure. Althoughvarious multiparameter optimization (MPO) strategies have guided CNSmedicinal chemistry for over a decade, existing frameworks rely heavilyon heuristic cutoffs and offer limited interpretability across chemicallydiverse scaffolds. Here, we introduce a next generation CNS-MPO framework─Aragen-iMPO,(A-iMPO)─which was developed using 5,129 curated compoundsthrough an integrated workflow combining explainable machine learning,rigorous descriptor selection, and low-dimensional discriminant mapping.This yielded six chemically intuitive features capturing polarity,ionization, size, rigidity, and electronic distribution. The resultingscore provides a transparent discriminant function enabling directcompound prioritization through a simple threshold rule. Across internaland external validation sets, A-iMPO outperformed established CNS-focusedscoring methods while maintaining mechanistic interpretability, providinga practical and design ready tool for CNS drug discovery.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"2055–2065"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Novel Phosphodiesterase-2 Inhibitors Discovered via Structure-Based Virtual Screening Targeting the Allosteric GAF-B Domain 通过基于结构的虚拟筛选发现针对变构GAF-B结构域的新型磷酸二酯酶2抑制剂

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-21 DOI: 10.1021/acsmedchemlett.6c00292

Charles Adeniran, Gadam Myratgeldiyev, Fang Zheng, Chang-Guo Zhan

{"title":"Novel Phosphodiesterase-2 Inhibitors Discovered via Structure-Based Virtual Screening Targeting the Allosteric GAF-B Domain","authors":"Charles Adeniran, Gadam Myratgeldiyev, Fang Zheng, Chang-Guo Zhan","doi":"10.1021/acsmedchemlett.6c00292","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00292","url":null,"abstract":"Phosphodiesterase-2 (PDE2) regulates intracellular cAMPand cGMPsignaling and is an important therapeutic target. In this study, weperformed the first virtual screening campaign targeting the allostericGAF-B domain of PDE2 to identify novel allosteric inhibitors. Unlikeconventional virtual screening methods based mainly on calculatedbinding energies, our approach incorporated binding mode analysisto rerank the top 5000 compounds according to the number of hydrogen-bondingand π–π stacking interactions with GAF-B residues.Experimental testing identified various novel PDE2 inhibitors, includingcompound 1 (IC50 = 0.77 μM)selective for PDE2 over other PDE isoforms. The reranking strategyyielded high hit rates of 62%, 51%, 29%, and 14% at inhibition thresholdsof 25%, 30%, 40%, and 50%, respectively. These findings demonstratethat incorporation of binding mode analysis into virtual screeningworkflows can substantially improve hit identification and may providea valuable strategy for future virtual screening campaigns againstPDE2 and other therapeutic targets.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"1994–2001"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148915851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Crystal Structure of the Sigma-2 Receptor Complexed with Investigational Drug Zervimesine (CT1812) Sigma-2受体与研究药物Zervimesine （CT1812）复合物的晶体结构

IF 3.9 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-07 DOI: 10.1021/acsmedchemlett.6c00215

Gary C. Look, Dominic Gilzer, Franziska Preuss, Jan Wollenhaupt, Julius Nitsche, Jérôme Amaudrut, Savina Malancona, Christian A.G.N. Montalbetti, Anthony O. Caggiano, Mary E. Hamby

{"title":"Crystal Structure of the Sigma-2 Receptor Complexed with Investigational Drug Zervimesine (CT1812)","authors":"Gary C. Look, Dominic Gilzer, Franziska Preuss, Jan Wollenhaupt, Julius Nitsche, Jérôme Amaudrut, Savina Malancona, Christian A.G.N. Montalbetti, Anthony O. Caggiano, Mary E. Hamby","doi":"10.1021/acsmedchemlett.6c00215","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00215","url":null,"abstract":"The investigationaldrug zervimesine (CT1812) is an allostericsmall molecule modulator of the sigma-2 receptor (S2R), known as transmembraneprotein 97 (TMEM97), currently in clinical development for Alzheimer’sdisease and dementia with Lewy bodies. In Phase 2 trials, consistentfavorable trends across outcome measures were observed for Alzheimer’sdisease (NCT03507790), dementia with Lewy Bodies (NCT05225415), andanother indication, dry AMD (NCT05893537). The crystal structure ofS2R complexed with zervimesine to 2.74 Å resolution reveals thisinvestigational therapeutic bound in the binding site of S2R analogousto that seen previously with other S2R ligands, and is consistentwith binding affinity data from a S2R competition assay. The structuralinteractions by which zervimesine binds with S2R are illuminated,which may shed light on the potential structure–function relationshipunderlying the favorable effects of zervimesine seen preclinicallyand clinically, and may foster the design of future S2R modulatorsfor neurodegenerative conditions.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 9","pages":"1925–1932"},"PeriodicalIF":3.9,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148915741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0