Journal of Medicinal Chemistry最新文献

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Development of Novel Silicon-Based Hydrophobic Tags (SiHyT) for Targeted Proteins Degradation
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-12-02 DOI: 10.1021/acs.jmedchem.4c0227310.1021/acs.jmedchem.4c02273
Lan Ma, Kun Zhang, Ziqi Huang, Yuda Guo, Ning Liu, Jia Chen, Xinyue Wang, Ying Liu, Mei Li, Jinxiao Li, Cheng Yang*, Shuangwei Liu* and Guang Yang*, 
{"title":"Development of Novel Silicon-Based Hydrophobic Tags (SiHyT) for Targeted Proteins Degradation","authors":"Lan Ma,&nbsp;Kun Zhang,&nbsp;Ziqi Huang,&nbsp;Yuda Guo,&nbsp;Ning Liu,&nbsp;Jia Chen,&nbsp;Xinyue Wang,&nbsp;Ying Liu,&nbsp;Mei Li,&nbsp;Jinxiao Li,&nbsp;Cheng Yang*,&nbsp;Shuangwei Liu* and Guang Yang*,&nbsp;","doi":"10.1021/acs.jmedchem.4c0227310.1021/acs.jmedchem.4c02273","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02273https://doi.org/10.1021/acs.jmedchem.4c02273","url":null,"abstract":"<p >Recent advances in targeted protein degradation (TPD) have propelled it to the forefront of small molecular drug discovery. Among these, hydrophobic tagging (HyT) strategies have garnered significant interest. Carbon-based hydrophobic tags have been recognized as effective Hyts for degrading a variety of target proteins. In this study, we introduce a novel class of potential EGFR degraders for the first time, which combine Gefitinib with silicon-based hydrophobic tags (SiHyT). The most promising candidate, degrader <b>7</b>, which links Gefitinib to a simple TBDPS silyl ether, has shown efficacy in degrading mutant EGFRs via the ubiquitin-proteosome system (UPS) both in vitro and in vivo. Notably, degrader <b>7</b> exhibits enhanced oral bioavailability owing to its superior metabolic stability compared to traditional carbon-based Hyts. Mechanistically, it was revealed that degrader <b>7</b> disrupts EGFR stability by dissociating the EGFR-HSP90 complex and recruiting E3 ligase, RNF149. More importantly, the potent and selective PD-L1 and BTK degraders were discovered successfully by utilizing the SiHyT strategy. The development of these innovative SiHyT compounds could broaden the repertoire of HyTs, enhancing the future design of TPD agents.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"21344–21363 21344–21363"},"PeriodicalIF":6.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142842380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Novel Benzimidazole Derivatives as Potent Inhibitors of Microsomal Prostaglandin E2 Synthase 1 for the Potential Treatment of Inflammation, Pain, and Fever
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-12-02 DOI: 10.1021/acs.jmedchem.4c0188310.1021/acs.jmedchem.4c01883
Azize Gizem Ergül, Paul M. Jordan, Philipp Dahlke, Nur Banu Bal, Abdurrahman Olğaç, Orhan Uludağ, Oliver Werz*, Burcu Çalışkan* and Erden Banoglu*, 
{"title":"Novel Benzimidazole Derivatives as Potent Inhibitors of Microsomal Prostaglandin E2 Synthase 1 for the Potential Treatment of Inflammation, Pain, and Fever","authors":"Azize Gizem Ergül,&nbsp;Paul M. Jordan,&nbsp;Philipp Dahlke,&nbsp;Nur Banu Bal,&nbsp;Abdurrahman Olğaç,&nbsp;Orhan Uludağ,&nbsp;Oliver Werz*,&nbsp;Burcu Çalışkan* and Erden Banoglu*,&nbsp;","doi":"10.1021/acs.jmedchem.4c0188310.1021/acs.jmedchem.4c01883","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01883https://doi.org/10.1021/acs.jmedchem.4c01883","url":null,"abstract":"<p >Microsomal prostaglandin E<sub>2</sub> synthase 1 (mPGES-1) is a promising target for treating inflammatory diseases and pain. This study introduces a novel series of benzimidazoles, with the most potent analogs exhibiting IC<sub>50</sub> values of 0.27–7.0 nM in a cell-free assay for prostaglandin (PG)E<sub>2</sub> production. Compound <b>44</b> (AGU654) demonstrated remarkable selectivity for mPGES-1 (IC<sub>50</sub> = 2.9 nM) over COX-1, COX-2, 5-LOX, and FLAP, along with excellent bioavailability. Metabololipidomics analysis with activated human monocyte-derived macrophages and human whole blood revealed that AGU654 selectively suppresses PGE<sub>2</sub> production triggered by bacterial exotoxins while sparing other prostaglandins. Furthermore, <i>in vivo</i> studies showed that AGU654 significantly alleviated fever, inflammation, and inflammatory pain in preclinical guinea pig models, suggesting that it could be an effective strategy for managing inflammatory diseases. In conclusion, these benzimidazole derivatives warrant further exploration into new and alternative analogs, potentially uncovering novel compounds with a favorable pharmacological profile possessing significant anti-inflammatory and analgesic properties.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"21143–21162 21143–21162"},"PeriodicalIF":6.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
A Novel Substituted Benzo[g]quinoxaline-Based Cyclometalated Ru(II) Complex as a Biocompatible Membrane-Targeted PDT Colon Cancer Stem Cell Agent
IF 7.3 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-12-02 DOI: 10.1021/acs.jmedchem.4c02357
Alicia Marco, Jana Kasparkova, Delia Bautista, Hana Kostrhunova, Natalia Cutillas, Lenka Markova, Vojtech Novohradsky, José Ruiz, Viktor Brabec
{"title":"A Novel Substituted Benzo[g]quinoxaline-Based Cyclometalated Ru(II) Complex as a Biocompatible Membrane-Targeted PDT Colon Cancer Stem Cell Agent","authors":"Alicia Marco, Jana Kasparkova, Delia Bautista, Hana Kostrhunova, Natalia Cutillas, Lenka Markova, Vojtech Novohradsky, José Ruiz, Viktor Brabec","doi":"10.1021/acs.jmedchem.4c02357","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02357","url":null,"abstract":"Herein, we describe and investigate biological activity of three octahedral ruthenium(II) complexes of the type [Ru(C<sup>∧</sup>N)(phen)<sub>2</sub>]<sup>+</sup>, <b>RuL1</b>–<b>RuL3</b>, containing a π-expansive cyclometalating substituted benzo[<i>g</i>]quinoxaline ligand (C<sup>∧</sup>N ligand) (phen = 1,10-phenanthroline). Compounds <b>RuL1</b>–<b>RuL3</b> in cervical, melanoma, and colon human cancer cells exhibit high phototoxicity after irradiation with light (particularly blue), with the phototoxicity index reaching 100 for the complex <b>RuL2</b> in most sensitive HCT116 cells. <b>RuL2</b> accumulates in the cellular membranes. If irradiated, it induces lipid peroxidation, likely connected with photoinduced ROS generation. Oxidative damage to the fatty acids leads to the attenuation of the membranes, the activation of caspase 3, and the triggering of the apoptotic pathway, thus implementing membrane-localized photodynamic therapy. <b>RuL2</b> is the first photoactive ruthenium-based complex capable of killing the hardly treatable colon cancer stem cells, a highly resilient subpopulation within a heterogeneous tumor mass, responsible for tumor recurrence and the metastatic progression of cancer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"79 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
A Novel Substituted Benzo[g]quinoxaline-Based Cyclometalated Ru(II) Complex as a Biocompatible Membrane-Targeted PDT Colon Cancer Stem Cell Agent
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-12-02 DOI: 10.1021/acs.jmedchem.4c0235710.1021/acs.jmedchem.4c02357
Alicia Marco, Jana Kasparkova, Delia Bautista, Hana Kostrhunova, Natalia Cutillas, Lenka Markova, Vojtech Novohradsky, José Ruiz* and Viktor Brabec*, 
{"title":"A Novel Substituted Benzo[g]quinoxaline-Based Cyclometalated Ru(II) Complex as a Biocompatible Membrane-Targeted PDT Colon Cancer Stem Cell Agent","authors":"Alicia Marco,&nbsp;Jana Kasparkova,&nbsp;Delia Bautista,&nbsp;Hana Kostrhunova,&nbsp;Natalia Cutillas,&nbsp;Lenka Markova,&nbsp;Vojtech Novohradsky,&nbsp;José Ruiz* and Viktor Brabec*,&nbsp;","doi":"10.1021/acs.jmedchem.4c0235710.1021/acs.jmedchem.4c02357","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02357https://doi.org/10.1021/acs.jmedchem.4c02357","url":null,"abstract":"<p >Herein, we describe and investigate biological activity of three octahedral ruthenium(II) complexes of the type [Ru(C<sup>∧</sup>N)(phen)<sub>2</sub>]<sup>+</sup>, <b>RuL1</b>–<b>RuL3</b>, containing a π-expansive cyclometalating substituted benzo[<i>g</i>]quinoxaline ligand (C<sup>∧</sup>N ligand) (phen = 1,10-phenanthroline). Compounds <b>RuL1</b>–<b>RuL3</b> in cervical, melanoma, and colon human cancer cells exhibit high phototoxicity after irradiation with light (particularly blue), with the phototoxicity index reaching 100 for the complex <b>RuL2</b> in most sensitive HCT116 cells. <b>RuL2</b> accumulates in the cellular membranes. If irradiated, it induces lipid peroxidation, likely connected with photoinduced ROS generation. Oxidative damage to the fatty acids leads to the attenuation of the membranes, the activation of caspase 3, and the triggering of the apoptotic pathway, thus implementing membrane-localized photodynamic therapy. <b>RuL2</b> is the first photoactive ruthenium-based complex capable of killing the hardly treatable colon cancer stem cells, a highly resilient subpopulation within a heterogeneous tumor mass, responsible for tumor recurrence and the metastatic progression of cancer.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"21470–21485 21470–21485"},"PeriodicalIF":6.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.4c02357","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Brain Penetrant NLRP3 Inhibitors: The Discovery of a Panacea?
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-12-02 DOI: 10.1021/acs.jmedchem.4c0284610.1021/acs.jmedchem.4c02846
David Harrison*, 
{"title":"Brain Penetrant NLRP3 Inhibitors: The Discovery of a Panacea?","authors":"David Harrison*,&nbsp;","doi":"10.1021/acs.jmedchem.4c0284610.1021/acs.jmedchem.4c02846","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02846https://doi.org/10.1021/acs.jmedchem.4c02846","url":null,"abstract":"<p >The NLRP3 inflammasome has attracted much interest as a drug target; however, many of the first wave of inhibitors were derived from a single aryl sulfonylurea starting point. The physicochemical properties of this molecule and most derivatives are not amenable to high brain penetration, thus limiting their potential effectiveness against disease targets where this is required. The disclosure of a novel pyridazine phenol scaffold facilitated a second wave of research toward brain-penetrant molecules, which may enable the discovery of novel treatments for Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and cardiometabolic diseases.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"20776–20779 20776–20779"},"PeriodicalIF":6.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
MPCD: A Multitask Graph Transformer for Molecular Property Prediction by Integrating Common and Domain Knowledge
IF 7.3 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-12-02 DOI: 10.1021/acs.jmedchem.4c02193
Xixi Yang, Yanjing Duan, Zhixiang Cheng, Kun Li, Yuansheng Liu, Xiangxiang Zeng, Dongsheng Cao
{"title":"MPCD: A Multitask Graph Transformer for Molecular Property Prediction by Integrating Common and Domain Knowledge","authors":"Xixi Yang, Yanjing Duan, Zhixiang Cheng, Kun Li, Yuansheng Liu, Xiangxiang Zeng, Dongsheng Cao","doi":"10.1021/acs.jmedchem.4c02193","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02193","url":null,"abstract":"Molecular property prediction with deep learning often employs self-supervised learning techniques to learn common knowledge through masked atom prediction. However, the common knowledge gained by masked atom prediction dramatically differs from the graph-level optimization objective of downstream tasks, which results in suboptimal problems. Particularly for properties with limited data, the failure to consider domain knowledge results in a direct search in an immense common space, rendering it infeasible to identify the global optimum. To address this, we propose MPCD, which enhances pretraining transferability by aligning the optimization objectives between pretraining and fine-tuning with domain knowledge. MPCD also leverages multitask learning to improve data utilization and model robustness. Technically, MPCD employs a relation-aware self-attention mechanism to capture molecules’ local and global structures comprehensively. Extensive validation demonstrates that MPCD outperforms state-of-the-art methods for absorption, distribution, metabolism, excretion, and toxicity (ADMET) and physicochemical prediction across various data sizes.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"27 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
4-Substituted-2-Thiazole Amides as Viral Replication Inhibitors of Alphaviruses
IF 7.3 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-12-02 DOI: 10.1021/acs.jmedchem.4c01073
Atefeh Garzan, S. Kaleem Ahmed, Nicole N. Haese, Gauthami Sulgey, Samuel Medica, Jessica L. Smith, Sixue Zhang, Fahim Ahmad, Shuklendu Karyakarte, Lynn Rasmussen, Victor DeFilippis, Babu Tekwani, Robert Bostwick, Mark J. Suto, Alec J. Hirsch, Thomas E. Morrison, Mark T. Heise, Corinne E. Augelli-Szafran, Daniel N. Streblow, Ashish K. Pathak, Omar Moukha-Chafiq
{"title":"4-Substituted-2-Thiazole Amides as Viral Replication Inhibitors of Alphaviruses","authors":"Atefeh Garzan, S. Kaleem Ahmed, Nicole N. Haese, Gauthami Sulgey, Samuel Medica, Jessica L. Smith, Sixue Zhang, Fahim Ahmad, Shuklendu Karyakarte, Lynn Rasmussen, Victor DeFilippis, Babu Tekwani, Robert Bostwick, Mark J. Suto, Alec J. Hirsch, Thomas E. Morrison, Mark T. Heise, Corinne E. Augelli-Szafran, Daniel N. Streblow, Ashish K. Pathak, Omar Moukha-Chafiq","doi":"10.1021/acs.jmedchem.4c01073","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01073","url":null,"abstract":"2-(Methylthio)-<i>N</i>-(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide <b>1</b> was identified as an inhibitor against Chikungunya virus (CHIKV) with good antiviral activity [EC<sub>50</sub> = 0.6 μM; EC<sub>90</sub> = 0.93 μM and viral titer reduction (VTR) of 6.9 logs at 10 μM concentration] with no observed cytotoxicity (CC<sub>50</sub> = 132 μM) in normal human dermal fibroblast (NHDF) cells. Structure–activity relationship (SAR) studies to further improve the potency, efficacy, and drug-like properties of <b>1</b> led to the discovery of a new potent inhibitor <i>N</i>-(4-(3-((4-cyanophenyl)amino)phenyl)thiazol-2-yl)-2-(methylthio)nicotinamide <b>26</b>, which showed a VTR of 8.7 logs at 10 μM against CHIKV and an EC<sub>90</sub> of 0.45 μM with considerably improved MLM stability (<i>t</i><sub>1/2</sub> = 74 min) as compared to <b>1</b>. Mechanism of action studies show that <b>26</b> inhibits alphavirus replication by blocking subgenomic viral RNA translation and structural protein synthesis. The <i>in vivo</i> efficacy studies of compound <b>26</b> on CHIKV infection in mice are reported.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"260 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Brain Penetrant NLRP3 Inhibitors: The Discovery of a Panacea?
IF 7.3 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-12-02 DOI: 10.1021/acs.jmedchem.4c02846
David Harrison
{"title":"Brain Penetrant NLRP3 Inhibitors: The Discovery of a Panacea?","authors":"David Harrison","doi":"10.1021/acs.jmedchem.4c02846","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02846","url":null,"abstract":"The NLRP3 inflammasome has attracted much interest as a drug target; however, many of the first wave of inhibitors were derived from a single aryl sulfonylurea starting point. The physicochemical properties of this molecule and most derivatives are not amenable to high brain penetration, thus limiting their potential effectiveness against disease targets where this is required. The disclosure of a novel pyridazine phenol scaffold facilitated a second wave of research toward brain-penetrant molecules, which may enable the discovery of novel treatments for Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and cardiometabolic diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"13 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
In Silico Tools to Score and Predict Cholesterol–Protein Interactions
IF 6.8 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-12-01 DOI: 10.1021/acs.jmedchem.4c0188510.1021/acs.jmedchem.4c01885
Anna Nguyen,  and , Alison E. Ondrus*, 
{"title":"In Silico Tools to Score and Predict Cholesterol–Protein Interactions","authors":"Anna Nguyen,&nbsp; and ,&nbsp;Alison E. Ondrus*,&nbsp;","doi":"10.1021/acs.jmedchem.4c0188510.1021/acs.jmedchem.4c01885","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01885https://doi.org/10.1021/acs.jmedchem.4c01885","url":null,"abstract":"<p >Cholesterol is structurally distinct from other lipids, which confers it with singular roles in membrane organization and protein function. As a signaling molecule, cholesterol engages in discrete interactions with transmembrane, peripheral, and certain soluble proteins to control cellular responses. Accordingly, the cholesterol–protein interface is central to cholesterol-related diseases and is an essential consideration in drug design. However, cholesterol’s hydrophobic, un-drug-like nature presents a unique challenge to traditional <i>in silico</i> analyses. In this Perspective, we survey a collection of tools designed to predict and evaluate cholesterol binding sites in proteins, including classical sequence motifs, molecular docking, template-based strategies, molecular dynamics simulations, and recent artificial intelligence approaches. We then comment on contemporary tools to evaluate ligand–protein interactions, their applicability to cholesterol, and the yet-untapped potential of cholesterol–protein interactions in human health and disease.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"20765–20775 20765–20775"},"PeriodicalIF":6.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.4c01885","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
In Silico Tools to Score and Predict Cholesterol–Protein Interactions
IF 7.3 1区 医学
Journal of Medicinal Chemistry Pub Date : 2024-12-01 DOI: 10.1021/acs.jmedchem.4c01885
Anna Nguyen, Alison E. Ondrus
{"title":"In Silico Tools to Score and Predict Cholesterol–Protein Interactions","authors":"Anna Nguyen, Alison E. Ondrus","doi":"10.1021/acs.jmedchem.4c01885","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01885","url":null,"abstract":"Cholesterol is structurally distinct from other lipids, which confers it with singular roles in membrane organization and protein function. As a signaling molecule, cholesterol engages in discrete interactions with transmembrane, peripheral, and certain soluble proteins to control cellular responses. Accordingly, the cholesterol–protein interface is central to cholesterol-related diseases and is an essential consideration in drug design. However, cholesterol’s hydrophobic, un-drug-like nature presents a unique challenge to traditional <i>in silico</i> analyses. In this Perspective, we survey a collection of tools designed to predict and evaluate cholesterol binding sites in proteins, including classical sequence motifs, molecular docking, template-based strategies, molecular dynamics simulations, and recent artificial intelligence approaches. We then comment on contemporary tools to evaluate ligand–protein interactions, their applicability to cholesterol, and the yet-untapped potential of cholesterol–protein interactions in human health and disease.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"8 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
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