MedChemComm最新文献

{"title":"Extension of multi-site analogue series with potent compounds using a bidirectional transformer-based chemical language model","authors":"Hengwei Chen, Atsushi Yoshimori and Jürgen Bajorath","doi":"10.1039/D4MD00423J","DOIUrl":"10.1039/D4MD00423J","url":null,"abstract":"<p >Generating potent compounds for evolving analogue series (AS) is a key challenge in medicinal chemistry. The versatility of chemical language models (CLMs) makes it possible to formulate this challenge as an off-the-beaten-path prediction task. In this work, we have devised a coding and tokenization scheme for evolving AS with multiple substitution sites (multi-site AS) and implemented a bidirectional transformer to predict new potent analogues for such series. Scientific foundations of this approach are discussed and, as a benchmark, the transformer model is compared to a recurrent neural network (RNN) for the prediction of analogues of AS with single substitution sites. Furthermore, the transformer is shown to successfully predict potent analogues with varying R-group combinations for multi-site AS having activity against many different targets. Prediction of R-group combinations for extending AS with potent compounds represents a novel approach for compound optimization.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 2527-2537"},"PeriodicalIF":3.597,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141506036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive framework for managing metabolic dysfunction-associated steatotic liver disease: analyzing novel risk factors and advances in nanotechnology-based treatments and diagnosis","authors":"Lucia M. Chávez-López, Gabriela I. Carballo-López, Karina del Carmen Lugo-Ibarra and Ana B. Castro-Ceseña","doi":"10.1039/D4MD00420E","DOIUrl":"10.1039/D4MD00420E","url":null,"abstract":"<p >Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a growing global health challenge requiring innovative approaches for effective management. This comprehensive review examines novel risk factors, including environmental pollutants like heavy metals, and underscores the complexity of personalized medicine tailored to individual patient profiles, influenced by gender and sex differences. Traditional treatments for MASLD, such as glucose- and lipid-lowering agents, show mixed results, highlighting the necessity for larger, long-term studies to establish safety and efficacy. Alternative therapies, including antioxidants, stem cells, and antiplatelets, although promising, demand extensive clinical trials for validation. This review highlights the importance of personalized medicine, considering individual variations and specific factors such as gender and sex, to optimize treatment responses. The shift from metabolic-associated fatty liver disease (MAFLD) to MASLD terminology underscores the metabolic components of the disease, aligning with the multiple-hit theory and highlighting the necessity for comprehensive risk factor management. Our vision advocates for an integrated approach to MASLD, encompassing extensive risk factor analysis and the development of safer, more effective treatments. Primary prevention and awareness initiatives are crucial in addressing the rising prevalence of MASLD. Future research must prioritize larger, long-term studies and personalized medicine principles to ensure the effective use of emerging therapies and technologies. The review underscores the need for continuous exploration and innovation, balancing the benefits and challenges of nanotechnology, to combat MASLD and improve patient outcomes comprehensively.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 2622-2642"},"PeriodicalIF":3.597,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141531762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of new 1,3-diphenylurea appended aryl pyridine derivatives as apoptosis inducers through c-MET and VEGFR-2 inhibition: design, synthesis, in vivo and in silico studies†","authors":"Heba A. Elsebaie, Mohamed S. Nafie, Haytham O. Tawfik, Amany Belal, Mohammed M. Ghoneim, Ahmad J. Obaidullah, Salwa Shaaban, Abdelmoneim A. Ayed, Mohamed El-Naggar, Ahmed B. M. Mehany and Moataz A. Shaldam","doi":"10.1039/D4MD00280F","DOIUrl":"10.1039/D4MD00280F","url":null,"abstract":"<p >Interest has been generated in VEGFR-2 and c-MET as potential receptors for the treatment of different malignancies. Using aryl pyridine derivatives with 1,3-diphenylurea attached, a number of promising dual VEGFR-2 and c-MET inhibitors were developed and synthesized. Regarding the molecular target, compounds <strong>2d</strong>, <strong>2f</strong>, <strong>2j</strong>, <strong>2k</strong>, and <strong>2n</strong> had potent IC<small>₅₀</small> values of 65, 24, 150, 170, and 18 nM against c-MET, respectively. Additionally, they had potent IC<small>₅₀</small> values of 310, 35, 290, 320, and 24 nM against VEGFR-2, respectively. Regarding cytotoxicity, compounds <strong>2d</strong>, <strong>2f</strong>, <strong>2j</strong>, <strong>2k</strong> and <strong>2n</strong> exhibited potent cytotoxicity against MCF-7 with IC<small>₅₀</small> values in the range 0.76–21.5 μM, and they showed promising cytotoxic activity against PC-3 with IC<small>₅₀</small> values in the range 1.85–3.42 μM compared to cabozantinib (IC<small>₅₀</small> = 1.06 μM against MCF-7 and 2.01 μM against PC-3). Regarding cell death, compound <strong>2n</strong> caused cell death in MCF-7 cells by 87.34-fold; it induced total apoptosis by 33.19% (8.04% for late apoptosis, 25.15% for early apoptosis), stopping their growth in the G<small>₂</small>/M phase, affecting the expression of apoptosis-related genes P53, Bax, caspases 3 and 9 and the anti-apoptotic gene, Bcl-2. <em>In vivo</em> study illustrated the anticancer activity of compound <strong>2n</strong> by reduction of tumor mass and volume, and the tumor inhibition ratio reached 56.1% with an improvement of hematological parameters. Accordingly, compound <strong>2n</strong> can be further developed as a selective target-oriented chemotherapeutic against breast cancer.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 2553-2569"},"PeriodicalIF":3.597,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141523106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-Sulfonylphenoxazines as neuronal calcium ion channel blockers†","authors":"Matthieu Schmit, Md. Mahadhi Hasan, Yashad Dongol, Fernanda C. Cardoso, Michael J. Kuiper, Richard J. Lewis, Peter J. Duggan and Kellie L. Tuck","doi":"10.1039/D4MD00336E","DOIUrl":"10.1039/D4MD00336E","url":null,"abstract":"<p >Neuropathic pain is a type of chronic pain, usually caused by nerve damage, that responds poorly to traditional pain therapies. The N-type calcium channel (Ca<small>_V</small>2.2) is a well-validated pharmacological target to treat this condition. In order to further improve the inhibition of the N-type calcium channel relative to previously described inhibitors, and also address their problematic instability in blood plasma, the development of <em>N</em>-sulfonylphenoxazines as new calcium channel inhibitors was pursued. A series of <em>N</em>-sulfonylphenoxazines bearing ammonium side chains were synthesised and tested for their ability to inhibit both Ca<small>_V</small>2.2 and Ca<small>_V</small>3.2 (T-type) neuronal ion channels. Compounds with low micromolar activity in Ca<small>_V</small>2.2 were identified, equivalent to the most effective reported for this class of bioactive, and calculations based on their physical and chemical characteristics suggest that the best performing compounds have a high likelihood of being able to penetrate the blood–brain barrier. Representative <em>N</em>-sulfonylphenoxazines were tested for their stability in rat plasma and were found to be much more resilient than the previously reported <em>N</em>-acyl analogues. These compounds were also found to be relatively stable in an <em>in vitro</em> liver microsome metabolism model, the first time that this has been investigated for this class of compound. Finally, molecular modelling of the Ca<small>_V</small>2.2 channel was used to gain an understanding of the mode of action of these inhibitors at a molecular level. They appear to bind in a part of the channel, in and above its selectivity filter, in a way that hinders its ability to undergo the conformational changes required to open and allow calcium ions to pass through.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 2400-2412"},"PeriodicalIF":3.597,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00336e?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141523105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Highly potent and selective phosphatidylinositol 4-kinase IIIβ inhibitors as broad-spectrum anti-rhinoviral agents","authors":"Avinash G. Vishakantegowda, Dasom Hwang, Prashant Chakrasali, Eunhye Jung, Joo-Youn Lee, Jin Soo Shin and Young-Sik Jung","doi":"10.1039/D4MD90022G","DOIUrl":"https://doi.org/10.1039/D4MD90022G","url":null,"abstract":"<p >Correction for ‘Highly potent and selective phosphatidylinositol 4-kinase IIIβ inhibitors as broad-spectrum anti-rhinoviral agents’ by Avinash G. Vishakantegowda <em>et al.</em>, <em>RSC Med. Chem.</em>, 2024, <strong>15</strong>, 704–719, https://doi.org/10.1039/D3MD00630A.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2196-2197"},"PeriodicalIF":3.597,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md90022g?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A method for estimation of plasma protein binding using diffusion ordered NMR spectroscopy (DOSY)†","authors":"Rachel Taylor, Thomas Swift, David Wilkinson and Kamyar Afarinkia","doi":"10.1039/D4MD00244J","DOIUrl":"10.1039/D4MD00244J","url":null,"abstract":"<p >The plasma protein binding (PPB) of a drug plays a key role in both its pharmacokinetic and pharmacodynamic properties. During lead optimisation, medium and high throughput methods for the early determination of PPB can provide important information about potential PKPD profile within a chemotype or between different chemotype series. Diffusion ordered spectroscopy (DOSY) is an NMR spectroscopic technique that measures the diffusion of a molecule through the magnetic field gradient, according to its molecular size/weight. Here, we describe the use of DOSY for a rapid and straightforward method to evaluate the PPB of drug molecules, using their binding to bovine serum albumin (BSA) as a model.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 2372-2379"},"PeriodicalIF":3.597,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141523107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New pyrazole–pyridazine hybrids as selective COX-2 inhibitors: design, synthesis, molecular docking, in silico studies and investigation of their anti-inflammatory potential by evaluation of TNF-α, IL-6, PGE-2 and NO in LPS-induced RAW264.7 macrophages†","authors":"Eman O. Osman, Nadia A. Khalil, Alaa Magdy and Yara El-Dash","doi":"10.1039/D4MD00135D","DOIUrl":"10.1039/D4MD00135D","url":null,"abstract":"<p >Hybrid-based design has gained significant interest in the development of novel active substances with anti-inflammatory properties. In this study, two series of new pyrazole–pyridazine-based hybrids, <strong>5a–f</strong> and <strong>6a–f</strong>, were designed and synthesized. Molecules containing pyrazole and pyridazine pharmacophores in a single molecule, each with a unique mechanism of action and different pharmacological characteristics, are believed to exert higher biological activity. The cell viability of all compounds was evaluated using MTT assay in LPS-induced RAW264.7 macrophages. <em>In vitro</em> COX-1 and COX-2 inhibition assays were performed for the investigation of the anti-inflammatory activity of target compounds. Trimethoxy derivatives <strong>5f</strong> and <strong>6f</strong> were the most active candidates, demonstrating higher COX-2 inhibitory action than celecoxib, with IC<small>₅₀</small> values of 1.50 and 1.15 μM, respectively. Bromo derivative <strong>6e</strong> demonstrated a COX-2 inhibitory activity comparable to celecoxib. Further, the ability of compounds <strong>5f</strong>, <strong>6e</strong>, and <strong>6f</strong> to inhibit the generation of specific pro-inflammatory cytokines and mediators, including nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and prostaglandin-E2 (PGE-2), in RAW264.7 macrophages stimulated by LPS was also estimated. Compounds <strong>5f</strong> and <strong>6f</strong> demonstrated the most potent activity. Morover, according to the investigation using molecular modeling studies, derivatives <strong>5f</strong> and <strong>6f</strong> showed respectable binding affinity towards the COX-2 active site compared to the reference ligand. Moreover, the ADME parameters, physicochemical characteristics, pharmacokinetic characteristics, and l of the most potent compounds were also computed.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 2692-2708"},"PeriodicalIF":3.597,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141523108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copper selective 8-aminoquinoline based tetradentate chelators as anticancer agents","authors":"Yingzhen Guan, Michel Nguyen, Anne Robert, Yan Liu and Bernard Meunier","doi":"10.1039/D4MD00171K","DOIUrl":"10.1039/D4MD00171K","url":null,"abstract":"<p >Cancer cell proliferation and metastasis are known to be dependent on angiogenesis which is regulated by several parameters including copper availability. Tetradentate monoquinoline (TDMQ) ligands constitute a series of chelators tailored to regulate copper homeostasis due to their specificity for copper(<small>II</small>) with respect to Cu(<small>I</small>) or other biometals like iron or zinc. One of these chelators, TDMQ20 efficiently inhibits both proliferation and migration of several human cancer cell lines, better than the reference drug 5-fluorouracil, and with higher selectivity indexes with respect to non-cancer human cells. The biological activity of TDMQ20 may be driven by the coordination chemistry of copper, and the ability of this chelator to restore copper homeostasis and its subsequent redox properties. The anticancer mechanism of action of TDMQ20 involves intracellular production of reactive oxygen species, drastic mitochondrial damages and induction of tumor cell apoptosis. These data support the selection of TDMQ20 as drug-candidate against several human cancers.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 3048-3056"},"PeriodicalIF":3.597,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00171k?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141523109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells†","authors":"Qin Xu, Maria Sharif, Edward James, Jack O. Dismorr, James H. R. Tucker, Benjamin E. Willcox and Youcef Mehellou","doi":"10.1039/D4MD00208C","DOIUrl":"10.1039/D4MD00208C","url":null,"abstract":"<p >The phosphoantigen (<em>E</em>)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) is an established activator of Vγ9/Vδ2 T cells and stimulates downstream effector functions including cytotoxicity and cytokine production. In order to improve its drug-like properties, we herein report the design, synthesis, serum stability, <em>in vitro</em> metabolism, and biological evaluation of a new class of symmetrical phosphonodiamidate prodrugs of methylene and difluoromethylene monophosphonate derivatives of HMBPP. These prodrugs, termed phosphonodiamidate ProPAgens, were synthesized in good yields, exhibited excellent serum stability (&gt;7 h), and their <em>in vitro</em> metabolism was shown to be initiated by carboxypeptidase Y. These phosphonodiamidate ProPAgens triggered potent activation of Vγ9/Vδ2 T cells, which translated into efficient Vγ9/Vδ2 T cell-mediated eradication of bladder cancer cells <em>in vitro</em>. Together, these findings showcase the potential of these phosphonodiamidate ProPAgens as Vγ9/Vδ2 T cell modulators that could be further developed as novel cancer immunotherapeutic agents.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 2462-2473"},"PeriodicalIF":3.597,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00208c?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141531763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging bounded datapoints to classify molecular potency improvements†","authors":"Zachary Fralish, Paul Skaluba and Daniel Reker","doi":"10.1039/D4MD00325J","DOIUrl":"10.1039/D4MD00325J","url":null,"abstract":"<p >Molecular machine learning algorithms are becoming increasingly powerful at predicting the potency of potential drug candidates to guide molecular discovery, lead series prioritization, and structural optimization. However, a substantial amount of inhibition data is bounded and inaccessible to traditional regression algorithms. Here, we develop a novel molecular pairing approach to process this data. This creates a new classification task of predicting which one of two paired molecules is more potent. This novel classification task can be accurately solved by various, established molecular machine learning algorithms, including XGBoost and Chemprop. Across 230 ChEMBL IC<small>₅₀</small> datasets, both tree-based and neural network-based “DeltaClassifiers” show improvements over traditional regression approaches in correctly classifying molecular potency improvements. The Chemprop-based deep DeltaClassifier outperformed all here evaluated regression approaches for paired molecules with shared and with distinct scaffolds, highlighting the promise of this approach for molecular optimization and scaffold-hopping.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 7","pages":" 2474-2482"},"PeriodicalIF":3.597,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00325j?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141190404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}