ACS Publications最新文献

{"title":"A Specialized and Enhanced Deep Generation Model for Active Molecular Design Targeting Kinases Guided by Affinity Prediction Models and Reinforcement Learning.","authors":"Xiaomeng Liu, Qin Li, Xiao Yan, Lingling Wang, Jiayue Qiu, Xiaojun Yao, Huanxiang Liu","doi":"10.1021/acs.jcim.5c00074","DOIUrl":"https://doi.org/10.1021/acs.jcim.5c00074","url":null,"abstract":"<p><p>Kinases are critical regulators in numerous cellular processes, and their dysregulation is linked to various diseases, including cancer. Thus, protein kinases have emerged as major drug targets at present, with approximately a quarter to a third of global drug development efforts focusing on kinases. Additionally, deep learning-based molecular generation methods have shown obvious advantages in exploring large chemical space and improving the efficiency of drug discovery. However, many current molecular generation models face challenges in considering specific targets and generating molecules with desired properties, such as target-related activity. Here, we developed a specialized and enhanced deep learning-based molecular generation framework named KinGen, which is specially designed for the efficient generation of small molecule kinase inhibitors. By integrating reinforcement learning, transfer learning, and a specialized reward module, KinGen leverages a binding affinity prediction model as part of its reward function, which allows it to accurately guide the generation process toward biologically relevant molecules with high target activity. This approach not only ensures that the generated molecules have desirable binding properties but also improves the efficiency of molecular optimization. The results demonstrate that KinGen can generate structurally valid, unique, and diverse molecules. The generated molecules exhibit binding affinities to the target that are comparable to known inhibitors, achieving an average docking score of -9.5 kcal/mol, which highlights the model's ability to design compounds with enhanced activity. These results suggest that KinGen has the potential to serve as an effective tool for accelerating kinase-targeted drug discovery efforts.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TCF7l2 Regulates Fatty Acid Chain Elongase HACD3 during Lipid-Induced Stress.","authors":"Atanu Mondal, Sandhik Nandi, Vipin Singh, Arnab Chakraborty, Indrakshi Banerjee, Sabyasachi Sen, Shrikanth S Gadad, Siddhartha Roy, Siddhesh S Kamat, Chandrima Das","doi":"10.1021/acs.biochem.4c00491","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00491","url":null,"abstract":"<p><p>The transcriptional regulation of metabolic genes is crucial for maintaining metabolic homeostasis under cellular stress conditions. Transcription factor 7-like 2 (TCF7l2 or TCF4) is associated with type 2 diabetes (T2D) and functions as a transcription factor for various gluconeogenic genes. T2D often coexists with metabolic dysfunction-associated steatotic liver disease (MASLD) due to common underlying mechanisms and shared risk factors such as insulin resistance and obesity. This study demonstrates the transcriptional regulation of one of the important fatty acid chain elongases implicated in T2D, HACD3 (encoded by <i>PTPLAD1</i> gene), under palmitic acid (PA)-induced stress conditions. We observed that TCF7l2 is associated with histone H3K4me3-binder protein TCF19 and is corecruited to the promoter of <i>PTPLAD1</i>. Upon PA treatment, the TCF19-TCF7l2 complex dissociates from the lipid chain elongase gene due to the reduced level of H3K4me3 enrichment, leading to <i>PTPLAD1</i> activation. Remarkably, gene expression analysis from the PA-injected mice and NAFLD patients indicates an anticorrelation whereby reduced TCF7l2 expression enhances HACD3-mediated chain elongation and triglyceride production, thereby promoting the development of MASLD. Our findings delineate that the epigenetic mechanism of activation of lipid chain elongase genes mediated by TCF7l2 in concert with TCF19 has important implications in metabolic disorders.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-Generation Products of <i>Trans</i>-2-Hexenal Ozonolyis: A New Look at the Mechanism.","authors":"Najoua Derbel, Alexander Alijah, Struan H Robertson, Thomas Lauvaux, Lilian Joly","doi":"10.1021/acs.jpca.4c07608","DOIUrl":"https://doi.org/10.1021/acs.jpca.4c07608","url":null,"abstract":"<p><p>The ozonolysis reaction of <i>trans</i>-2-hexenal was studied theoretically on the basis of highly accurate CCSD(T)-F12b/AVTZ energy values obtained in M06-2X/AVTZ preoptimized nuclear configurations. The kinetics was modeled with the help of the master equation solver MESMER. Apart from the expected stable oxidation products 1-butanal (17%) and glyoxal (35%), a secondary ozonide is formed on the glyoxal channel, which is the principal first-generation product (49%). It is further shown that glyoxal is created on two competing pathways, one of which leads to simultaneous production of the ester propylformate (18%). The inclusion of all of these mechanisms explains the experimental findings and identifies for the first time the origin of the experimental carbon deficit.</p>","PeriodicalId":59,"journal":{"name":"The Journal of Physical Chemistry A","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving p<i>K</i>_a Predictions with Reparameterized Force Fields and Free Energy Calculations.","authors":"Carter J Wilson, Vytautas Gapsys, Bert L de Groot","doi":"10.1021/acs.jctc.5c00031","DOIUrl":"https://doi.org/10.1021/acs.jctc.5c00031","url":null,"abstract":"<p><p>Given the growing interest in designing targeted covalent inhibitors, methods for rapidly and accurately probing p<i>K</i>_as─and, by extension, the reactivities─of target cysteines are highly desirable. Complementary to cysteine, histidine is similarly relevant due to its frequent presence in protein active sites and its unique ability to exist in two tautomeric states. Here, we demonstrate that nonequilibrium free energy calculations can accurately determine the p<i>K</i>_a values of both residues, often outperforming conventional predictors. Importantly, we find that (1) increasing the van der Waals radius of cysteine's sulfur atom, (2) modifying the backbone charges of histidine, and (3) introducing effective polarization by downscaling the side chain partial charges of both residues can all significantly improve p<i>K</i>_a prediction accuracy. Using the modified CHARMM36m force field on the full dataset reduces the prediction error from 2.12 ± 0.27 p<i>K</i> to 1.28 ± 0.15 p<i>K</i> and increases the correlation with experiment from 0.25 ± 0.09 to 0.58 ± 0.08. Similarly, using the modified Amber14SB force field decreases the error from 3.21 ± 0.29 p<i>K</i> to 1.69 ± 0.23 p<i>K</i> and improves the correlation from 0.15 ± 0.10 to 0.36 ± 0.10.</p>","PeriodicalId":45,"journal":{"name":"Journal of Chemical Theory and Computation","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IR Spectroscopy of 4-Aminobenzonitrile⁺-Ar_<i>n</i> (<i>n</i> = 0-2): Determination of the Activation Barrier for the π → NH Site-Switching Reaction.","authors":"Shino Yukumi, Otto Dopfer, Mitsuhiko Miyazaki","doi":"10.1021/acs.jpca.5c00730","DOIUrl":"https://doi.org/10.1021/acs.jpca.5c00730","url":null,"abstract":"<p><p>Information about the intermolecular potential energy surface for the interaction between solute and solvent molecules is required to understand the impact of solvation on reaction mechanisms and dynamics. In this study, we measured vibrational-specific infrared (IR) spectra of 4-aminobenzonitrile-(argon)_<i>n</i> cation clusters, 4ABN⁺-Ar_<i>n</i> (<i>n</i> = 1, 2), in the NH stretching range to elucidate the energetics of the photoionization-induced π → NH migration of Ar. The IR spectra of 4ABN⁺-Ar_<i>n</i> generated by resonant photoionization of neutral π-bonded clusters display the hydrogen-bonded NH₂ stretching vibration (ν_NH₂) only when intermolecular vibrational levels are excited. This is the first observation of Ar migration from the aromatic ring toward the NH₂ group upon photoionization in the <i>n</i> = 1 cluster. From the vibrational-level dependence of the IR spectra, the activation barrier heights are determined to be 21-47 (34 ± 13) and <27 cm^-1 for 4ABN⁺-Ar₁ and 4ABN⁺-Ar₂, respectively. The potential energy surfaces and mechanism of the Ar migration are discussed with the help of complementary density functional theory calculations.</p>","PeriodicalId":59,"journal":{"name":"The Journal of Physical Chemistry A","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MD Multi-Sector Selector: Recursive Extraction and Refinement of Molecular Dynamics Based Sectors Yields Two Sectors in p53 Tumor Suppressor Protein.","authors":"Christopher A Chiu, Sean Stetson, Kelly M Thayer","doi":"10.1021/acs.jpcb.4c08495","DOIUrl":"https://doi.org/10.1021/acs.jpcb.4c08495","url":null,"abstract":"<p><p>Allosteric signaling in proteins allows perturbations at one locale to modulate activity at an orthosteric distant site. This may explain how distal mutations disrupt protein activity and offer pathways for the development of allosteric therapeutics, a novel class of restorative compounds to reactivate native function. Despite the ubiquitous presence of allosteric control in nature and the promises that it holds for treating currently untreatable diseases, quantitative theory of the mechanism of allostery is lacking. Working to fill this critical gap, we have developed a novel method to identify groups of covarying residues which the sector hypothesis suggests are capable of transmitting allosteric signals in proteins. A major problem with sectors computed from covariance measures is the selection relies upon a full covariance matrix rather than on the covariance among the residues posited to be in the sector. We demonstrate a novel method which constructs sectors on the basis of cohesion within the residues in the sector to eliminate the incongruity between the sector idea and the way it is calculated. Furthermore, the refinement can be iteratively applied, enabling the extraction of more than one sector in a well-defined, systematic manner. In this study, we report on the development of MD multi-sector selector and its application to allosteric signaling in the tumor suppressor protein p53. We consider the implications of our findings on our long-term goal of allosterically reactivating mutant p53 as a means of curing cancer, and critically assess the broader applicability of MD multi-sector selector across diverse fields.</p>","PeriodicalId":60,"journal":{"name":"The Journal of Physical Chemistry B","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Robust Cu²⁺-Modified Black Phosphorus Nanoplatform for Enhanced Drug Delivery and Synergistic Multimodal Tumor Therapy via Metal Ion-Assisted π-π Interactions.","authors":"Kai Ling, Jianlan Bu, Weijie Huang, Wenyue Kang, Qingpeng Yuan, Bingchun Zeng, Chuanghong Liao, Qiunuan Zheng, Guangrong Zhang, Xuanjun Zheng, Zeyang Chen, Xiaohong Jiang, Rui Li, Tiantian Zhai, Hongyan Jiang","doi":"10.1021/acsami.4c22168","DOIUrl":"10.1021/acsami.4c22168","url":null,"abstract":"<p><p>The application of 2D nanomaterials for drug delivery via π-π interactions has been extensively investigated. However, these interactions often lack robustness in the presence of blood proteins due to the competitive binding of blood proteins, which results from strong π-π-stacking interactions with aromatic protein residues. This can lead to premature drug release and diminished therapeutic efficacy. To address this challenge, we developed a robust 2D delivery/therapeutic biomimetic nanoplatform that enhances the adsorption affinity and targeted delivery efficiency of the chemotherapeutic drug doxorubicin (DOX) by utilizing Cu²⁺-modified black phosphorus nanosheets (BP@Cu²⁺) through metal ion-assisted π-π interactions. The synergistic interactions between the π-electrons of BP and DOX, mediated by Cu²⁺ coordination, form a stable sandwiched π-cation-π stacking complex (BP@Cu²⁺/DOX). This metal-ion-bridged architecture significantly enhances the DOX loading capacity and minimizes premature release in serum. In the acidic tumor microenvironment, this interaction is disrupted, enabling controlled release of both DOX and Cu²⁺ ions. Furthermore, the encapsulation of the complex within tumor cell membranes significantly enhances the efficiency of tumor targeting, resulting in a biomimetic nanoplatform (BP@Cu²⁺/DOX-CMs). Combined with near-infrared laser irradiation, this nanoplatform achieves synergistic multimodal therapy by integrating phototherapy, chemotherapy, chemodynamic therapy, and cuproptosis to enhance antitumor efficacy. The study highlights the potential of metal ion-assisted π-π stacking interactions in the development of advanced 2D nanoplatforms, thereby paving the way for innovative biomedical applications utilizing conventional 2D nanomaterials.</p>","PeriodicalId":5,"journal":{"name":"ACS Applied Materials & Interfaces","volume":" ","pages":"19382-19400"},"PeriodicalIF":8.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Charged Insulating Skeleton-Enabled Deep Deposition and Robust Interface for Stable Lithium Metal Anodes.","authors":"Zhechen Fan, Pengrui Liang, Wenhui Wang, Kaiwen Qi, Shiyuan Chen, Xuan Ding, Yongchun Zhu","doi":"10.1021/acsami.4c18896","DOIUrl":"10.1021/acsami.4c18896","url":null,"abstract":"<p><p>Conductive 3D collectors for lithium metal anodes always lead to the direct deposition of lithium on top of the skeleton, which contributes to aggressive volume change and an unstable interface layer. Herein, we design a three-dimensional collector composed of an insulating glass fiber skeleton and conductive copper substrate (NGF@Cu) to guide a bottom-up deep deposition of lithium metal. This composite structure with abundant pores realizes a directed ion-electron path and deep lithium deposition, fully harnessing its internal space to accommodate lithium. After modification with amino silane, the positively charged insulating skeletons show a regulated distribution of anions and rapid transport of Li ions in the electrolyte and lead to the formation of robust LiF-rich SEI layers, thereby inhibiting the growth of dendrites and the accumulation of dead lithium. Consequently, symmetrical batteries assembled with charged glass fiber/copper collectors exhibit a long lifespan of over 1300 h, while full batteries with NCM811 cathodes exhibit a stable cycling performance of over 300 cycles at 0.5 C and good capacity retention at high rates. The fabrication of charged insulating 3D collectors provides inspiration for metal electrodes with high energy density and reversibility.</p>","PeriodicalId":5,"journal":{"name":"ACS Applied Materials & Interfaces","volume":" ","pages":"19501-19511"},"PeriodicalIF":8.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing Charge Collection of Tin-Based Perovskite Solar Cells by Optimizing the Buried Interface with a Multifunctional Self-Assembled Monolayer.","authors":"Junyu Qu, Xiaoxue Wang, Chuan Luo, Chenwu Zeng, Hangyu Zhou, Zihao Yang, Zhihao Zhang, Jialun Jin, Yuanfang Huang, Chao Ding, Cong Chen, Shengqiang Ren, Dewei Zhao","doi":"10.1021/acsami.5c01653","DOIUrl":"10.1021/acsami.5c01653","url":null,"abstract":"<p><p>Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) is a widely used hole transport material in inverted tin-based perovskite solar cells (Sn-PSCs). However, the efficiency and stability of these Sn-PSCs that utilize PEDOT:PSS are unsatisfactory, partly due to concerns about their mismatched work functions, hydrophobicity, and chemical interactions. Here, we introduce a self-assembled monolayer (SAM), (2-(7<i>H</i>-dibenzo[c,g]carbazol-7-yl)ethyl) phosphonic acid (2PADCB) as a multifunctional buffer molecule at the buried PEDOT:PSS/Sn perovskite interface. The phosphate group in the 2PADCB molecule reacts with the sulfur atom on the thiophene ring in PEDOT:PSS. This reaction process effectively anchors the SAM molecule firmly to the surface of PEDOT:PSS. Additionally, it reduces the binding sites between PEDOT and PSS, alleviating the acidification of the PEDOT:PSS surface and the poor conductivity caused by excessive PSS. Furthermore, the presence of two additional benzene rings in the 2PADCB molecule terminal group increases the electron density around Sn²⁺, thereby inhibiting its oxidation. Additionally, the hydrophobic characteristics of the 2PADCB molecule mitigate moisture infiltration from PEDOT:PSS, thereby protecting the degradation of Sn perovskite. Consequently, the Sn-PSCs based on the PEDOT:PSS/2PADCB film achieve a champion efficiency of 14.7%, higher than that of their pristine counterpart (12.5%). Moreover, the 2PADCB molecule improves the stability of the device by maintaining 90% of its initial efficiency after 160 h under 1 Sun illumination. Such enhancement in efficiency and stability is mainly attributed to the improved interface quality with the 2PADCB molecule, leading to better carrier transport and suppressed charge recombination at the buried PEDOT:PSS/Sn perovskite interface. Our work suggests that introducing the 2PADCB molecule at the PEDOT:PSS/perovskite interface is a promising method for efficient and stable Sn-PSCs.</p>","PeriodicalId":5,"journal":{"name":"ACS Applied Materials & Interfaces","volume":" ","pages":"19783-19794"},"PeriodicalIF":8.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Fiber-Reinforced Poly(ionic liquid) Solid Electrolyte with Low Flammability and High Conductivity for High-Performance Lithium-Metal Batteries.","authors":"Junyan Tang, En Chen, Dehua Wang, Wen Qin, Siyu Fang, Ting Xu, Junjie Liu, Mi Tang, Zhengbang Wang","doi":"10.1021/acsami.4c23109","DOIUrl":"10.1021/acsami.4c23109","url":null,"abstract":"<p><p>Construction of polymer-based solid electrolytes with both low flammability and high ionic conductivity for lithium-metal batteries is still a great challenge but highly desirable. Herein, we report on a series of fiber-reinforced poly(ionic liquid) solid electrolytes prepared through an <i>in situ</i> copolymerization of ionic liquid monomers (IL) and poly(ethylene glycol) diacrylate (PEGDA) units with different ratios inside a polyacrylonitrile (PAN) fiber membrane. Such PAN/Poly-IL-PEGDA composite electrolytes demonstrate promising low flammability due to the excellent fire-resistant feature of the employed IL units. Moreover, it is remarkable to see that the optimized PAN/Poly-IL-PEGDA-1 electrolyte also exhibits highly dense structure with low thickness (31 μm), high ionic conductivity (0.32 mS cm^-1 at 30 °C), and wide electrochemical window (up to 4.8 V). As a result, both LiFePO₄//Li and NCM//Li full cells with such an electrolyte exhibit both excellent rate capability and cycling stability. This study provides a simple strategy for preparing composite polymer electrolytes with low flammability and high conductivity for high-performance lithium-metal batteries.</p>","PeriodicalId":5,"journal":{"name":"ACS Applied Materials & Interfaces","volume":" ","pages":"19682-19691"},"PeriodicalIF":8.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}