Journal of Medicinal Chemistry最新文献

{"title":"Labeled and Label-Free Target Identifications of Natural Products.","authors":"Shuyu Wang, Yu Zhang, Ruizhi Yu, Yue Chai, Ruyun Liu, Jianqiang Yu, Zhuo Qu, Wannian Zhang, Chunlin Zhuang","doi":"10.1021/acs.jmedchem.4c01576","DOIUrl":"10.1021/acs.jmedchem.4c01576","url":null,"abstract":"<p><p>Target identification, employing chemical proteomics, constitutes a continuous challenging endeavor in the drug development of natural products (NPs). Understanding their targets is crucial for deciphering their mechanisms and developing potential probes or drugs. Identifications fall into two main categories: labeled and label-free techniques. Labeled methods use the molecules tagged with markers such as biotin or fluorescent labels to easily detect interactions with target proteins. Thorough structure-activity relationships are essential before labeling to avoid changes in the biological activity or binding specificity. In contrast, label-free technologies identify target proteins without modifying natural products, relying on changes in the stability, thermal properties, or precipitation in the presence or absence of these products. Each approach has its advantages and disadvantages, offering a comprehensive understanding of the mechanisms and therapeutic potential of the NPs. Here, we summarize target identification techniques for natural molecules, highlight case studies of notable NPs, and explore future applications and directions.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363448","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}

{"title":"Light-Controlled Anticancer Activity and Cellular Uptake of a Photoswitchable Cisplatin Analogue","authors":"Marta Stolarek, Kamil Kaminski, Marta Kaczor-Kamińska, Magdalena Obłoza, Piotr Bonarek, Anna Czaja, Magdalena Datta, Wojciech Łach, Mateusz Brela, Artur Sikorski, Janusz Rak, Maria Nowakowska, Krzysztof Szczubiałka","doi":"10.1021/acs.jmedchem.4c01575","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01575","url":null,"abstract":"A photoactive analogue of cisplatin was synthesized with two arylazopyrazole ligands, able to undergo <i>trans</i>–<i>cis</i>/<i>cis</i>–<i>trans</i> photoisomerizations. The <i>cis</i> photoisomer showed a dark half-life of 9 days. The cytotoxicities of both photoisomers of the complex were determined in several cancer and normal cell lines and compared to that of cisplatin. The <i>trans</i> photoisomer of the complex was much more cytotoxic than both the <i>cis</i> photoisomer and cisplatin, and was more toxic for cancer (4T1) than for normal (NMuMG) murine breast cells. 4T1 cell death occurred through necrosis. Photoisomerization of the <i>trans</i> and <i>cis</i> photoisomers internalized by the 4T1 cells increased and decreased their viability, respectively. The cellular uptake of the <i>trans</i> photoisomer was stronger than that of both the <i>cis</i> photoisomer and cisplatin. Both photoisomers interacted with DNA faster than cisplatin. The <i>trans</i> photoisomer was bound stronger by bovine serum albumin and induced a greater decrease in cellular glutathione levels than the <i>cis</i> photoisomer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488777","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}

{"title":"Identification of a Novel Protein Phosphatase 2A Activator, PPA24, as a Potential Therapeutic for FOLFOX-Resistant Colorectal Cancer.","authors":"Hannah Johnson, Amandeep Singh, Asif Raza, Congzhou M Sha, Jian Wang, Krishne Gowda, Zhihang Shen, Haritha Nair, Chenglong Li, Nikolay V Dokholyan, Satya Narayan, Arun K Sharma","doi":"10.1021/acs.jmedchem.4c01077","DOIUrl":"10.1021/acs.jmedchem.4c01077","url":null,"abstract":"<p><p>A series of compounds were designed utilizing molecular modeling and fragment-based design based upon the known protein phosphatase 2A (PP2A) activators, <b>NSC49L</b> and <b>iHAP1</b>, and evaluated for their ability to inhibit the viability of colorectal cancer (CRC) and folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX)-resistant CRC cells. <b>PPA24</b> (<b>19a</b>) was identified as the most cytotoxic compound with IC₅₀ values in the range of 2.36-6.75 μM in CRC and FOLFOX-resistant CRC cell lines. It stimulated PP2A activity to a greater extent, displayed lower binding energies through molecular docking, and showed higher binding affinity through surface plasmon resonance for PP2A catalytic subunit α than the known PP2A activators. <b>PPA24</b> dose-dependently induced apoptosis and oxidative stress, decreased the level of c-Myc expression, and synergistically potentiated cytotoxicity when combined with gemcitabine and cisplatin. Furthermore, a <b>PPA24</b>-encapsulated nanoformulation significantly inhibited the growth of CRC xenografts without systemic toxicities. Together, these results signify the potential of <b>PPA24</b> as a novel PP2A activator and a prospective therapeutic for CRC and FOLFOX-resistant CRC.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615230","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}

{"title":"Development of an Intravenously Stable Disulfide-Rich Peptide for the Treatment of Chemotherapy-Induced Neuropathic Pain","authors":"Tianmiao Li, Han-Shen Tae, Shen Chen, Xiao Li, Jiazhen Liang, Teng Pan, Zixuan Zhang, Tao Jiang, David J. Adams, Rilei Yu","doi":"10.1021/acs.jmedchem.4c00974","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c00974","url":null,"abstract":"α-conotoxins (α-Ctxs), a class of disulfide-rich conopetides, are excellent drug leads due to their small size, high selectivity, and potency for specific membrane receptors and ion channels involved in pain transmission. However, their high susceptibility to proteolytic degradation limits their therapeutic potential. In this study, we designed and synthesized a series of conformationally stable analogues of α-Ctx Mr1.1[S4Dap] using various structural optimization strategies. The Mr1.1[S4Dap, C16Pen] analogue maintained potency at human α9α10 nicotinic acetylcholine receptors, with a half-maximal inhibitory concentration (IC₅₀) of 4 nM. It exhibited over a 5-fold increase in serum stability compared to Mr1.1[S4Dap], without disrupting its overall conformation. Furthermore, intravenous application of Mr1.1[S4Dap, C16Pen] showed potent analgesic activity in oxaliplatin-induced cold allodynia, indicating a high potential for drug development. Overall, the results from this study provide valuable insights for optimizing the serum stability of disulfide-rich peptides in future therapeutic applications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489312","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}

{"title":"Construction of New MRI Contrast Agents for Spatiotemporal Visualization of Nitric Oxide in Ischemia/Reperfusion Organs.","authors":"Libang Zhang, Yuze Sun, Zonglu Gao, Lin Wang, Mei Jing, Zhengsheng Yan, Anning Xu, Xun Yuan, Yihua Zhang, Jianbing Wu, Jian Zhang, Zhiqi Yin, Zhangjian Huang","doi":"10.1021/acs.jmedchem.4c01813","DOIUrl":"10.1021/acs.jmedchem.4c01813","url":null,"abstract":"<p><p>Noninvasive and real-time nitric oxide (NO) visualization <i>in vivo</i> is still a challenge. Herein, we constructed a series of NO-responsive magnetic resonance imaging (MRI) contrast agents <b>Gd1b</b>-<b>e</b> by modifying Gd-DO3A using a bis-pyridyl-ethylamine side chain as a signal-amplifying moiety and <i>o</i>-phenylenediamine as a NO-responsive linker. It was found that <b>Gd1b</b>, <b>d</b>, and <b>e</b> can form macromolecular ternary complexes (Gd-Zn²⁺-HSA) with high longitudinal relaxivity (<i>r</i>₁) (12.2-16.2 mM^-1 s^-1). Once reacting with NO, the <i>o</i>-phenylenediamine linker was hydrolyzed to produce a small molecular Gd complex with sharply decreased <i>r</i>₁ (4.7-6.3 mM^-1 s^-1). Among them, <b>Gd1d</b> with a desirable pharmacokinetic profile (<i>t</i>_1/2 = 5.91 h) could clearly distinguish the ischemia-reperfusion (IR) liver with excessive NO in rats. Meanwhile, the temporarily reduced amount of NO in the IR liver and brain by the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl could enhance the signal of <b>Gd1d</b>, suggesting anticipated NO-responsive property. This research offers a new avenue for insight into the NO spatiotemporal property in multiple IR organs.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370219","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}

{"title":"Effects of SARS-CoV-2 Main Protease Mutations at Positions L50, E166, and L167 Rendering Resistance to Covalent and Noncovalent Inhibitors.","authors":"Andrey Kovalevsky, Annie Aniana, Rodolfo Ghirlando, Leighton Coates, Victoria N Drago, Lauren Wear, Oksana Gerlits, Nashaat T Nashed, John M Louis","doi":"10.1021/acs.jmedchem.4c01781","DOIUrl":"10.1021/acs.jmedchem.4c01781","url":null,"abstract":"<p><p>SARS-CoV-2 propagation under nirmatrelvir and ensitrelvir pressure selects for main protease (MPro) drug-resistant mutations E166V (DRM2), L50F/E166V (DRM3), E166A/L167F (DRM4), and L50F/E166A/L167F (DRM5). DRM2-DRM5 undergoes N-terminal autoprocessing to produce mature MPro with dimer dissociation constants (<i>K</i>_dimer) 2-3 times larger than that of the wildtype. Co-selection of L50F restores catalytic activity of DRM2 and DRM4 from ∼10 to 30%, relative to that of the wild-type enzyme, without altering <i>K</i>_dimer. Binding affinities and thermodynamic profiles that parallel the drug selection pressure, exhibiting significant decreases in affinity through entropy/enthalpy compensation, were compared with GC373. Reorganization of the active sites due to mutations observed in the inhibitor-free DRM3 and DRM4 structures as compared to MPro^WT may account for the reduced binding affinities, although DRM2 and DRM3 complexes with ensitrelvir are almost identical to MPro^WT-ensitrelvir. Chemical reactivity changes of the mutant active sites due to differences in electrostatic and protein dynamics effects likely contribute to losses in binding affinities.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379413","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}

{"title":"Medicinal Chemistry Education: Molecular Level Understanding of All Medicinal Properties and Innovative Strategies","authors":"Sankar K. Guchhait","doi":"10.1021/acs.jmedchem.4c02460","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02460","url":null,"abstract":"Study the past if you would define the future. – Confucius Figure 1. Expertise-based career transitions to medicinal chemistry. Medicinal chemistry – a molecular level understanding of what an exogeneous molecule can do in the human body as well as what the body can do to the exogeneous molecule. Consideration of P3 properties – pharmacodynamics, physicochemical (ADMET-relevant), and pharmacokinetic profile. This requires a change from the conventional “structure–activity relationship” (SAR) to a comprehensive “structure–function relationship” (SFR) approach to all P3 properties of new investigational molecules. Critical molecular medicinal insight into the function of drugs, treatment regimens, clinical candidates. Drug Annotations and Patent Highlights published in the &lt;i&gt;Journal of Medicinal Chemistry&lt;/i&gt; are useful to consider for teaching. Combination therapy to network polypharmacology interference. Analysis of molecular mechanisms associated with efficacy versus adverse drug reactions (ADRs) and drug-resistance issues. In the design and discovery of novel therapeutic agents, knowledge of “medicinophores” can be introduced. A structural motif that is responsible for improving major medicinal properties of investigated molecules can be termed as a “medicinophore”, while a pharmacophore is responsible for ligand-binding to biological macromolecules, and a chromophore represents a molecular part, a group, or an atom in a material that absorbs a particular wavelength of visible light and as a result reflects the color of the material. A range of property-focused strategies with innovative thinking and hypothesis-driven design rationale in drug discovery efforts. Computer-based predictions: AI, ML, DL, cluster-based analysis, molecular docking, molecular dynamics, various filters for physicochemical properties to create molecular medicinal value, and molecular physicochemical property descriptors. Chemical reactions, reagents, processes, logic in chemical (organic) synthesis, retrosynthesis, development of reaction methods and synthetic approaches, access to molecular diversity, and late-stage functionalization. Greener syntheses, green chemistry principles, greener reagents, solvents, and methods, and metrics. Intellectual property rights and patent law. Biophysical studies for evaluation of biological/medicinal properties and in vitro assay protocols, structure–function optimization, and in vivo experiments. Knowledge of using advanced scientific (analytical, spectroscopic, and others) instruments in drug discovery. Hands-on experience with experiments to gain skills in laboratory and research techniques and practical exposure to course contents. Real-life research experience through research projects focusing on particular therapeutic problems and the design, synthesis, and discovery of new bioactive agents or internships for drug discovery R&amp;D experience in the pharmaceutical industry. This article has not yet been cited by other publica","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489090","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}

{"title":"Medicinal Chemistry Education: Teaching an Old Dog with New Tricks.","authors":"Manu Sharma","doi":"10.1021/acs.jmedchem.4c02244","DOIUrl":"10.1021/acs.jmedchem.4c02244","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363449","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}

{"title":"Immune Checkpoint-Modulating Photosensitizer That Targets BRD4 for Cancer Photoimmunotherapy","authors":"Peixia Li, Yayin Du, Jingru Qiu, Qiaoyun Jiang, Weijia Chen, Xinke Zhang, Guiling Li, Donghai Li, Gang Shan","doi":"10.1021/acs.jmedchem.4c01362","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01362","url":null,"abstract":"Photodynamic therapy is an efficient approach to promote cytotoxic T lymphocyte tumor infiltration to convert immunologically cold tumors into hot tumors through the induction of immunogenic cell death . However, tumors usually overexpress immune checkpoints such as PD-L1 to suppress T lymphocyte antitumor activity and evade immune surveillance. Therefore, the design of efficient photosensitizers to overcome checkpoint-mediated immune evasion is highly necessary. In this work, we report the design of <b>BRD-PS</b>, a BRD4-targeting photosensitizer, as a new class of immunomodulatory photosensitizer termed an immune checkpoint-modulating photosensitizer, to solve this issue. On one hand, <b>BRD-PS</b> induces immunogenic pyroptosis and ferroptosis to promote the activation and tumor infiltration of cytotoxic T cells. On the other hand, <b>BRD-PS</b> suppresses the expression of PD-L1 to avoid immune evasion. This work demonstrated the feasibility of utilizing a single photosensitizer to simultaneously induce immunogenic cell death and PD-L1 downregulation for synergistic cancer photoimmunotherapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489085","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}

{"title":"The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvβ6 Inhibitor for Fibrosis","authors":"Bryce A. Harrison, James E. Dowling, Matthew G. Bursavich, Dawn M. Troast, Katherine M. Chong, Kristopher N. Hahn, Cheng Zhong, Kristen M. Mulvihill, Hanh Nguyen, Meghan F. Monroy, Qi Qiao, Brian Sosa, Siavash Mostafavi, Inese Smukste, Dooyoung Lee, Laura Cappellucci, Elizabeth H. Konopka, Patrycja Nowakowski, Lukasz Stawski, Mayra Senices, Minh Hai Nguyen, Parmita S. Kapoor, Lia Luus, Andrew Sullivan, Andrea Bortolato, Mats Svensson, Eugene R. Hickey, Kyle D. Konze, Tyler Day, Byungchan Kim, Ana Negri, Aleksey I. Gerasyuto, Terence I. Moy, Min Lu, Adrian S. Ray, Liangsu Wang, Dan Cui, Fu-Yang Lin, Blaise Lippa, Bruce N. Rogers","doi":"10.1021/acs.jmedchem.4c01851","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01851","url":null,"abstract":"Inhibition of integrin αvβ6 is a promising approach to the treatment of fibrotic disease such as idiopathic pulmonary fibrosis. Screening a small library combining head groups that stabilize the bent-closed conformation of integrin αIIbβ3 with αv integrin binding motifs resulted in the identification of hit compounds that bind the bent-closed conformation of αvβ6. Crystal structures of these compounds bound to αvβ6 and related integrins revealed opportunities to increase potency and selectivity, and these efforts were accelerated using accurate free energy perturbation (FEP+) calculations. Optimization of PK parameters including permeability, bioavailability, clearance, and half-life resulted in the discovery of development candidate MORF-627, a highly selective inhibitor of αvβ6 that stabilizes the bent-closed conformation and has good oral PK. Unfortunately, the compound showed toxicity in a 28-day NHP safety study, precluding further development. Nevertheless, MORF-627 is a useful tool compound for studying the biology of integrin αvβ6.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489087","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}