ACS Central Science最新文献

{"title":"Docking 14 Million Virtual Isoquinuclidines against the μ and κ Opioid Receptors Reveals Dual Antagonists–Inverse Agonists with Reduced Withdrawal Effects","authors":"Seth F. Vigneron,&nbsp;Shohei Ohno,&nbsp;Joao Braz,&nbsp;Joseph Y. Kim,&nbsp;Oh Sang Kweon,&nbsp;Chase Webb,&nbsp;Christian B. Billesbølle,&nbsp;Karthik Srinivasan,&nbsp;Karnika Bhardwaj,&nbsp;John J. Irwin*,&nbsp;Aashish Manglik*,&nbsp;Allan I. Basbaum*,&nbsp;Jonathan A. Ellman* and Brian K. Shoichet*,&nbsp;","doi":"10.1021/acscentsci.5c0005210.1021/acscentsci.5c00052","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00052https://doi.org/10.1021/acscentsci.5c00052","url":null,"abstract":"<p >Large library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving many interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration and targeted docking of isoquinuclidines. These “natural-product-like” molecules are rare in current libraries and are functionally congested, making them interesting as receptor probes. Using a modular, four-component reaction scheme, we built and docked a virtual library of over 14.6 million isoquinuclidines against both the μ- and κ-opioid receptors (MOR and KOR, respectively). Synthesis and experimental testing of 18 prioritized compounds found nine ligands with low μM affinities. Structure-based optimization revealed low- and sub-nM antagonists and inverse agonists targeting both receptors. Cryo-electron microscopy structures illuminate the origins of activity on each target. In mouse behavioral studies, a potent joint MOR-antagonist and KOR-inverse-agonist reversed morphine-induced analgesia, phenocopying the MOR-selective antioverdose agent naloxone. Encouragingly, the isoquinuclidine induced less severe opioid-withdrawal symptoms versus naloxone and did not induce conditioned-place aversion, reflecting reduced dysphoria, consistent with its KOR-inverse agonism. The strengths and weaknesses of bespoke library docking and of docking for opioid receptor polypharmacology will be considered.</p><p >Docking a virtual isoquinuclidine library revealed dual opioid receptor ligands. Structure-guided optimization led to potent antagonists that reverse morphine <i>in vivo</i> with reduced withdrawal effects.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 5","pages":"770–790 770–790"},"PeriodicalIF":12.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.5c00052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Ruibing Lv,&nbsp;Lei Sun,&nbsp;Zhenghang Luo,&nbsp;Yujie Song,&nbsp;Shuo Li and Qi Zhang,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 4","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":12.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144420181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Hao Yang,&nbsp;Xiaolin Liu,&nbsp;Moeen Meigooni,&nbsp;Li Zhang,&nbsp;Jitong Ren,&nbsp;Qian Chen,&nbsp;Mark Losego,&nbsp;Emad Tajkhorshid*,&nbsp;Jeffrey S. Moore* and Charles M. Schroeder*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 4","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":12.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.4c01849","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144420187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Casey J. Chen,&nbsp; and ,&nbsp;Evan R. Williams*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 4","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":12.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00306","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144420229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combustion Resistant Borohydrides and Their Chemical Interactions with Li-Metal Surfaces: An Experimental and Theoretical Study","authors":"Anton W. Tomich*,&nbsp;Stephen Proctor,&nbsp;Moon Young Yang,&nbsp;Jianjun Chen,&nbsp;Yifan Zhao,&nbsp;Edward Chen,&nbsp;Tridip Das,&nbsp;Boris V. Merinov,&nbsp;William A. Goddard III*,&nbsp;Juchen Guo* and Vincent Lavallo*,&nbsp;","doi":"10.1021/acscentsci.5c0004310.1021/acscentsci.5c00043","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00043https://doi.org/10.1021/acscentsci.5c00043","url":null,"abstract":"<p >Borohydrides are important molecular entities for a myriad of applications from organic synthesis to components of functional materials and devices. All borohydrides have been thought to be susceptible to spontaneous ignition when exposed to a flame. Herein we demonstrate that this is not always true by identifying several borohydride rich materials that are resistant to combustion when contacted with a torch. One of these materials is a Li⁺ salt of a carborane anion that depending on its coordination environment exists as a unique ionic liquid that has a nearly naked Li⁺ countercation. This has provided us with the first opportunity to spectroscopically probe the interactions of such carborane anions with Li metal in a solvent free environment. We found that this carborane anion is immune to deleterious reduction at Li-metal surfaces, as evidenced by XPS, EDS and SEM analysis of the Li-Metal surface after exposure to the ionic liquid. Additionally, NMR analysis of the ionic liquid after stirring it with Li powder shows no reaction. Calculations show that the cage skeleton is reduced at the surface monolayer, but as the reduced form is removed from contact with Li-metal, the cage reverts to the <i>closo</i>-form, demonstrating reversibility.</p><p >Among a series of combustion resistant borohydrides, we describe the synthesis of a carboranyl ionic liquid whose chemical compatibility against Li metal is investigated through experiment and theory.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 5","pages":"734–741 734–741"},"PeriodicalIF":12.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.5c00043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Facile Access to Hindered Ethers via Photoinduced O–H Bond Insertions","authors":"Yu Zhang,&nbsp;Xinyu Han,&nbsp;Dong Li,&nbsp;Dinggang Wang,&nbsp;Jinxin Wang,&nbsp;Xin Luan,&nbsp;Shao-Fei Ni*,&nbsp;Shoubhik Das* and Wei-Dong Zhang*,&nbsp;","doi":"10.1021/acscentsci.5c0009910.1021/acscentsci.5c00099","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00099https://doi.org/10.1021/acscentsci.5c00099","url":null,"abstract":"<p >The synthesis of the hindered and polyfluorinated dialkyl ethers poses challenges owing to the bulkiness of tertiary alcohols and the low nucleophilicity of polyfluorinated alcohols. Additionally, associated competitive side reactions always provide poor reactivities. Although certain strategies, such as electrocatalytic decarboxylation and hydroalkoxylation, have been explored, a straightforward method for obtaining ethers with structural diversity remains elusive. In this study, we have exploited the photoinduced approach that involves the <i>in situ</i> formation of singlet carbenes followed by O–H insertions to access the hindered and polyfluorinated ethers with congested or polyfluorinated alcohols. Moreover, other nucleophiles such as phenols, H₂O, thiols, silanols, tributyltin hydride, <i>etc</i>., are also tolerable to obtain valuable products. The gram-scale synthesis of marketed drugs and the modification of complex molecules demonstrate the practicality of this approach. The detailed mechanistic studies have elucidated the key intermediates and reaction mechanism, which were distinct from traditional metal-carbenoid O–H insertions.</p><p >In this study, a photoinduced approach to access the hindered and polyfluorinated ethers are exploited through the <i>in situ</i> formation of singlet carbenes and subsequent O−H insertions.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 5","pages":"742–752 742–752"},"PeriodicalIF":12.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.5c00099","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Marcos Dantus​,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 4","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":12.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.5c00556","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144420182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Facile Access to Hindered Ethers via Photoinduced O-H Bond Insertions.","authors":"Yu Zhang, Xinyu Han, Dong Li, Dinggang Wang, Jinxin Wang, Xin Luan, Shao-Fei Ni, Shoubhik Das, Wei-Dong Zhang","doi":"10.1021/acscentsci.5c00099","DOIUrl":"10.1021/acscentsci.5c00099","url":null,"abstract":"<p><p>The synthesis of the hindered and polyfluorinated dialkyl ethers poses challenges owing to the bulkiness of tertiary alcohols and the low nucleophilicity of polyfluorinated alcohols. Additionally, associated competitive side reactions always provide poor reactivities. Although certain strategies, such as electrocatalytic decarboxylation and hydroalkoxylation, have been explored, a straightforward method for obtaining ethers with structural diversity remains elusive. In this study, we have exploited the photoinduced approach that involves the <i>in situ</i> formation of singlet carbenes followed by O-H insertions to access the hindered and polyfluorinated ethers with congested or polyfluorinated alcohols. Moreover, other nucleophiles such as phenols, H₂O, thiols, silanols, tributyltin hydride, <i>etc</i>., are also tolerable to obtain valuable products. The gram-scale synthesis of marketed drugs and the modification of complex molecules demonstrate the practicality of this approach. The detailed mechanistic studies have elucidated the key intermediates and reaction mechanism, which were distinct from traditional metal-carbenoid O-H insertions.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 5","pages":"742-752"},"PeriodicalIF":12.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Lukas Lüthy,&nbsp;Leon Gabor Sacha Thies,&nbsp;Konstantin Nikolaus Beitl,&nbsp;Moritz Hansen,&nbsp;Joshua McManus,&nbsp;Muhammad Afzal,&nbsp;Lukas Schrangl,&nbsp;Susanne Bloch,&nbsp;Guruprakash Subbiahdoss,&nbsp;Erik Reimhult*,&nbsp;Christina Schäffer* and Erick M. Carreira*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 4","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":12.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.4c02184","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144420186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Sourav Mondal,&nbsp;Julia Netz,&nbsp;David Hunger,&nbsp;Simon Suhr,&nbsp;Biprajit Sarkar,&nbsp;Joris van Slageren,&nbsp;Andreas Köhn and Alessandro Lunghi*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 4","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":12.7,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acscentsci.4c02139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144420189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}