Chemical Biology & Drug Design最新文献_第2页

1,2,3-Triazole Tethered Spiro[Indoline-Oxirane] Derivatives Induce Anticancer Effects in Human Hepatoma Cells

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-26 DOI: 10.1111/cbdd.70091

Shashikala Mariswamy Rajesh, Prasanna Doddakunche Shivaramu, Chandra Sekhar Bhol, Toreshettahally R. Swaroop, Habbanakuppe D. Preetham, Rajaghatta N. Suresh, Arunachalam Chinnathambi, Chandramohan Govindasamy, Sulaiman Ali Alharbi, Veeresha Gowda Shalini, Kwang Seok Ahn, Shobith Rangappa, Kanchugarakoppal S. Rangappa

{"title":"1,2,3-Triazole Tethered Spiro[Indoline-Oxirane] Derivatives Induce Anticancer Effects in Human Hepatoma Cells","authors":"Shashikala Mariswamy Rajesh, Prasanna Doddakunche Shivaramu, Chandra Sekhar Bhol, Toreshettahally R. Swaroop, Habbanakuppe D. Preetham, Rajaghatta N. Suresh, Arunachalam Chinnathambi, Chandramohan Govindasamy, Sulaiman Ali Alharbi, Veeresha Gowda Shalini, Kwang Seok Ahn, Shobith Rangappa, Kanchugarakoppal S. Rangappa","doi":"10.1111/cbdd.70091","DOIUrl":"https://doi.org/10.1111/cbdd.70091","url":null,"abstract":"<div>\u0000 \u0000 <p>Epoxides are well-known compounds as anticancer agents. In this article, we present the synthesis of novel 3′-phenyl-1-((1-aryl-1<i>H</i>-1,2,3-triazol-5-yl)methyl)spiro[indoline-3,2′-oxiran]-2-one derivatives by the regioselective reaction of sulfur ylides with 1,2,3-triazole-tethered isatins and their anticancer effects on hepatocellular carcinoma (HCC) cells HepG2 and HCCLM3. The cell viability assays indicated that <b>RR-01</b> and <b>RR-07</b> had emerged as the most potent cytotoxic agents on the tested cell lines. Colony formation and migration assay results confirmed the anticancer effects of these compounds by inhibiting the formation of colonies and migration. Further, nuclear fragmentation staining assay showed that the compounds induce apoptosis. Acridine orange staining assays showed that our lead candidates (<b>RR-01</b> and <b>RR-07</b>) induced autophagy in liver cancer cells.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Oridonin Alleviates Doxorubicin-Induced Cardiotoxicity by Inhibiting p38 MAPK/MMP3 Signaling Pathway

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-24 DOI: 10.1111/cbdd.70093

Xingyuan Hou, Suifen Xie, Ni Zhou, Shanshan Wei, Yuanying Yang, Ziheng Luo, Sa Liu, Jian Liu, Ning Xie, Wenqun Li, Bikui Zhang

{"title":"Oridonin Alleviates Doxorubicin-Induced Cardiotoxicity by Inhibiting p38 MAPK/MMP3 Signaling Pathway","authors":"Xingyuan Hou, Suifen Xie, Ni Zhou, Shanshan Wei, Yuanying Yang, Ziheng Luo, Sa Liu, Jian Liu, Ning Xie, Wenqun Li, Bikui Zhang","doi":"10.1111/cbdd.70093","DOIUrl":"https://doi.org/10.1111/cbdd.70093","url":null,"abstract":"<div>\u0000 \u0000 <p>Although doxorubicin (DOX) is an efficient chemotherapeutic drug for human tumors, severe cardiotoxicity restricts its clinical use. Oridonin (Ori), a bioactive component isolated from <i>Isodon rubescens</i> (Hemsl.) H. Hara, possesses potent anti-inflammatory and anticancer potentials. Therefore, our study aimed to evaluate the protective effects of Ori against DOX-induced cardiotoxicity. DIC models were established in vivo and in vitro. The action targets and pharmaceutical mechanism of Ori against DIC were comprehensively examined by network pharmacology, RNA-sequencing, and experimental validation. Ori relieved Dox-induced cell apoptosis in vitro and in vivo. A total of 7084 DEGs, 196 Ori, and 8172 DIC targets were screened by transcriptomics and network pharmacology, respectively. The three sets contained 11 intersection genes, including Ccl2, Myc, Mmp3, Egfr, p38 MAPK (MAPK14), Esr1, Tnf, Jun, Cdk1, Alb, and Ccnd1. The experimental results showed that Ori significantly decreased MMP-3 activity and the expression of p38 MAPK, thereby attenuating myocardial apoptosis and inflammatory infiltration. This study suggests that Ori is a potential therapeutic agent for DOX-induced cardiotoxicity that exerts its effects by inhibiting the p38 MAPK/MMP-3 signaling pathway.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Pyrazoles: A Master Key to Tackle Multidrug-Resistant Acinetobacter baumannii and Its Structure Activity Relationship Studies

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-24 DOI: 10.1111/cbdd.70092

Saraswati Sharma, Sahana Raju, Santosh Kumar Verma, Kamal, Rameshwari Verma, Piyush Kumar Thakur, Kothanahally S. Sharath Kumar

{"title":"Pyrazoles: A Master Key to Tackle Multidrug-Resistant Acinetobacter baumannii and Its Structure Activity Relationship Studies","authors":"Saraswati Sharma, Sahana Raju, Santosh Kumar Verma,  Kamal, Rameshwari Verma, Piyush Kumar Thakur, Kothanahally S. Sharath Kumar","doi":"10.1111/cbdd.70092","DOIUrl":"https://doi.org/10.1111/cbdd.70092","url":null,"abstract":"<div>\u0000 \u0000 <p>Infections caused by Gram-negative bacteria within the ESKAPE group pose significant treatment challenges. These bacteria feature effective efflux pumps and possess lipopolysaccharides in their outer membranes, as well as a thin peptidoglycan layer measuring 5–10 nm in thickness. <i>Acinetobacter baumannii</i> (<i>A. baumannii</i>), a Gram-negative bacterium, is a significant contributor to serious infections acquired in hospitals and communities, representing a substantial risk to human health. This bacterium has developed resistance to nearly all existing antibiotics, and in the past 50 years, no new antibacterial class has been introduced for treating <i>A. baumannii</i> infections, highlighting an urgent necessity for the development of new antibacterials. The unique structural framework and adaptable features of the pyrazole ring attract researchers to develop new antibiotics. The present study outlines the advancements made over the last decade in pyrazole-containing derivatives that exhibit a wide range of antibacterial activity against various bacterial strains. Specifically, we discuss the effectiveness of diverse pyrazole derivatives against multidrug-resistant <i>A. baumannii</i> strains and explore various aspects of the structure–activity relationship (SAR). This compilation of data could serve as an excellent platform for designing and developing new pyrazole-based small molecules to target the growth of <i>A. baumannii</i>.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Discovery of New 4-Aminoquinoline–Thiazolidinone Hybrid Analogs as Antiproliferative Agents Inhibiting TLR4–LPS-Mediated Migration in Triple-Negative Breast Cancer Cells

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-24 DOI: 10.1111/cbdd.70089

S. K. Batin Rahaman, Satyajit Halder, Kuldeep K. Roy, Pallab K. Halder, Utsab Debnath, Kuladip Jana

{"title":"Discovery of New 4-Aminoquinoline–Thiazolidinone Hybrid Analogs as Antiproliferative Agents Inhibiting TLR4–LPS-Mediated Migration in Triple-Negative Breast Cancer Cells","authors":"S. K. Batin Rahaman, Satyajit Halder, Kuldeep K. Roy, Pallab K. Halder, Utsab Debnath, Kuladip Jana","doi":"10.1111/cbdd.70089","DOIUrl":"https://doi.org/10.1111/cbdd.70089","url":null,"abstract":"<div>\u0000 \u0000 <p>The Toll-like receptor 4 (TLR4) signaling pathway plays a leading role in triggering proinflammatory responses by targeting lipopolysaccharide (LPS) molecules from different bacteria. Meanwhile, it is also expressed at higher levels in breast cancer cells than in normal breast tissue. After LPS binding, it initiates downstream signaling pathways that promote inflammation and cell apoptosis. Thus, targeting TLR4–LPS presents a promising dual therapeutic strategy for breast cancer treatment by not only inhibiting tumor growth but also reducing inflammation within the tumor microenvironment. To achieve this, the discovery of a new antiinflammatory agent is needed to reduce LPS-mediated cancer cell proliferation and migration. In this study, a series of 4-aminoquinoline–thiazolidinone hybrid analogs (4a-m) have been synthesized to explore their antiinflammatory as well as anticancer activity to find a new lead. Among them, 4e revealed the most promising antiinflammatory (IC50 = 2.38 ± 0.77 μM) as well as anticancer activity (IC50 = 3.26 ± 1.06 μM) in RAW 267.7 cell line and triple-negative breast cancer (TNBC) cell line, respectively. Further structure–activity relationship study followed by MD simulation analysis was carried out to identify probable binding residues of TLR4 which may play a significant role in developing antiinflammatory activity for promoting cell apoptosis in cancer cells.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Potential Role of Hesperidin in Improving Experimental Pulmonary Arterial Hypertension in Rats via Modulation of the NF-κB Pathway

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-20 DOI: 10.1111/cbdd.70068

Jun He, Jun-hua Liao

{"title":"Potential Role of Hesperidin in Improving Experimental Pulmonary Arterial Hypertension in Rats via Modulation of the NF-κB Pathway","authors":"Jun He, Jun-hua Liao","doi":"10.1111/cbdd.70068","DOIUrl":"10.1111/cbdd.70068","url":null,"abstract":"<div>\u0000 \u0000 <p>This study was designed to evaluate the therapeutic effects of hesperidin, an anti-inflammatory compound, on pulmonary arterial hypertension (PAH). A PAH rat model was established using monocrotaline (MCT, 60 mg/kg). Next, the experimental animals were assigned into the following four groups (<i>n</i> = 6 per group): Control group, MCT group, MCT + H20 group (20 mg/kg hesperidin), and MCT + H40 group (40 mg/kg hesperidin). According to the experimental outcomes, the PAH rat model was built successfully. In PAH animals, hesperidin significantly reduced right ventricular systolic pressure, Fulton index, and mean pulmonary arterial pressure. Concurrently, it improved pulmonary artery velocity-time integral and acceleration time, as well as alleviated pulmonary artery and right ventricular remodeling. On a molecular level, hesperidin inhibited the expression of vascular endothelial-cadherin, alpha-smooth muscle actin, matrix metalloproteinase-9, and transforming growth factor beta. Also, hesperidin downregulated pro-inflammatory cytokines such as interleukin (IL)-6, IL-1β, IL-18, chemokine C-C motif ligand 2, and C-X-C motif chemokine ligand 1 levels, and reduced the number of CD68+ cells in tissue samples. Further analysis revealed that hesperidin could inhibit the activation of p-IκB-α and p-p65 in samples induced by MCT. Collectively, these findings suggest that hesperidin may inhibit inflammation through the NF-κB pathway, thereby improving experimental PAH in rats induced by MCT.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Artesunate Suppresses the Migration and Invasion of Thyroid Cancer Cells via Upregulating PTEN to Block M2 Polarization of Tumor-Associated Macrophages

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-18 DOI: 10.1111/cbdd.70076

Zhiwei Xu, Xiuping Li, Daoping Zhuang

{"title":"Artesunate Suppresses the Migration and Invasion of Thyroid Cancer Cells via Upregulating PTEN to Block M2 Polarization of Tumor-Associated Macrophages","authors":"Zhiwei Xu, Xiuping Li, Daoping Zhuang","doi":"10.1111/cbdd.70076","DOIUrl":"https://doi.org/10.1111/cbdd.70076","url":null,"abstract":"<div>\u0000 \u0000 <p>Immunotherapy holds promise for thyroid cancer (TC) treatment. In the context of our previous findings that artesunate (ART) could inhibit the migration and invasion of TC cells through phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), this study was engineered to investigate whether ART regulates the tumor microenvironment in TC. THP-1 cells were differentiated into M0 macrophages by the induction of 100 ng/mL of phorbol 12-myristate 13-acetate and transfected as needed. M0 macrophages were treated with different concentrations of ART (10 and 20 μM) for 24 h. The co-culture of macrophages and TC cells was conducted. Flow cytometry and enzyme-linked immunosorbent assay were used to identify M2 macrophages. The viability, migration, and invasion of TC cells were detected by cell counting kit-8, wound healing, and transwell assays. The mRNA or protein expressions of examined genes were measured by quantitative real-time polymerase chain reaction or Western blot. In co-cultured macrophages, protein expressions of CD206, CD163, and Arginase-1, as well as the secretion of IL-10 and CCL18, were promoted, but phosphatase and tensin homolog (PTEN) mRNA expression was inhibited, which were reversed by different concentrations of ART. In the co-culture system, 20 μM of ART downregulated mRNA expressions of CD206, CD163, and Arginase-1 in macrophages and diminished viability, migration, invasion, as well as ratios of p-PI3K/PI3K and p-Akt/Akt in TC cells, which were offset by PTEN deletion in macrophages. Collectively, ART suppresses the migration and invasion of TC cells via inhibiting the PI3K/Akt pathway by PTEN upregulation-blocked M2 polarization of tumor-associated macrophages.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143645739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Non-Hydroxamate Inhibitors of IspC Enzyme in the MEP Pathway: Structural Insights and Drug Development Potential MEP 通路中 IspC 酶的非羟氨酸盐抑制剂：结构洞察力与药物开发潜力

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-18 DOI: 10.1111/cbdd.70086

Yaqing Zhou, Jili Wang, Yong Sun, Yarui Cheng, Wenhai Wu

{"title":"Non-Hydroxamate Inhibitors of IspC Enzyme in the MEP Pathway: Structural Insights and Drug Development Potential","authors":"Yaqing Zhou, Jili Wang, Yong Sun, Yarui Cheng, Wenhai Wu","doi":"10.1111/cbdd.70086","DOIUrl":"https://doi.org/10.1111/cbdd.70086","url":null,"abstract":"<div>\u0000 \u0000 <p>1-Deoxy-D-xylulose-5-phosphate reductoisomerase (IspC) is a key enzyme in the MEP pathway, essential for many bacteria, human pathogens, and plants, thus being an attractive drug target. Fosmidomycin, a potent IspC inhibitor with hydroxamate metal-binding pharmacophores (MBPs), has entered clinical trials for malaria but is hampered by pharmacokinetic and toxicity issues of the hydroxamate fragment. This has led to increased interest in non-hydroxamate inhibitors. This review focuses on the crystal structure and active-site binding mode of IspC, and the structural types, inhibitory activities, and structure–activity relationships of non-hydroxamate IspC inhibitors. Early attempts to design such inhibitors involved direct removal or replacement of the hydroxamate MBPs, with varying results. Lipophilic inhibitors, bisubstrate inhibitors, and those developed for herbicidal applications have shown promise. However, challenges remain due to the sensitivity of the enzyme active site to ligand interactions. Future research could draw from other metalloenzyme studies to develop novel and efficient non-hydroxamate IspC inhibitors.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Small Molecule Inhibitors Targeting Cdc2-Like Kinase 4: Advances, Challenges, and Opportunities

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-17 DOI: 10.1111/cbdd.70087

Yu Jiang, Zihua Tang, Minggao Jiang, Jing Wang, Yanhai Wang

{"title":"Small Molecule Inhibitors Targeting Cdc2-Like Kinase 4: Advances, Challenges, and Opportunities","authors":"Yu Jiang, Zihua Tang, Minggao Jiang, Jing Wang, Yanhai Wang","doi":"10.1111/cbdd.70087","DOIUrl":"https://doi.org/10.1111/cbdd.70087","url":null,"abstract":"<div>\u0000 \u0000 <p>Cdc2-like kinase 4 (Clk4), a key member of the CMGC kinase family, plays a crucial role in alternative splicing, which profoundly influences various physiological processes, including cellular signaling, proliferation, and survival. Its involvement in these vital functions has positioned Clk4 as an important target for therapeutic intervention in a range of diseases, such as neurodegenerative disorders, viral and parasitic infections, and cancer. This review highlights recent advancements in Clk4 inhibitors, covering both natural, and synthetic compounds. It further examines the core scaffolds and essential functional groups of Clk4 small-molecule inhibitors, emphasizing the most promising chemical structures. Additionally, the review explores the structure–activity relationships (SARs) and molecular binding modes of existing Clk4 inhibitors, offering insights and strategies for the development of novel Clk4-targeted drugs. This review highlights recent advancements in small molecule inhibitors targeting Clk4, emphasizing their potential in treating cancers and neurodegenerative diseases. It explores SARs, binding modes, and challenges in developing selective Clk4 inhibitors, offering insights for future therapeutic strategies.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Synthesis of New Thiazole-Pyrazole Analogues: Molecular Modelling, Antiproliferative/Antiviral Activities, and ADME Studies

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-14 DOI: 10.1111/cbdd.70090

Hind A. Siddiq, Mohammed A. Imam, Shaker T. Alsharif, Roba M. S. Attar, Renad Almughathawi, Nadiyah M. Alshammari, Nuha M. Halawani, Nashwa M. El-Metwaly

{"title":"Synthesis of New Thiazole-Pyrazole Analogues: Molecular Modelling, Antiproliferative/Antiviral Activities, and ADME Studies","authors":"Hind A. Siddiq, Mohammed A. Imam, Shaker T. Alsharif, Roba M. S. Attar, Renad Almughathawi, Nadiyah M. Alshammari, Nuha M. Halawani, Nashwa M. El-Metwaly","doi":"10.1111/cbdd.70090","DOIUrl":"https://doi.org/10.1111/cbdd.70090","url":null,"abstract":"<div>\u0000 \u0000 <p>Twelve thiazole-pyrazole analogues <b>4</b>, <b>6</b>, and <b>8</b> were synthesized by introducing various pyrazole systems into the core, 2-((4-acetylphenyl)amino)-4-methylthiazole (<b>2</b>), through many synthetic approaches. The density functional theory (DFT) study of the synthesized analogues revealed coincided configurations of their highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO), except for the nitro derivatives, in which the intramolecular charge-transfer (CT) may be denoted as π → π* and <i>n</i> → π*. In addition, the in vitro antiproliferative efficacy towards some cancer cell lines was examined (Panc-1, HT-29, MCF-7) and the non-cancerous (WI-38), using Dasatinib (Reference). The analogues <b>4c</b> and <b>4d</b> demonstrated the most potent anticancer effect, particularly against Panc-1 and MCF-7 cells. Moreover, the antiviral activity against H5N1, using a plaque reduction assay, showed that analogue <b>6a</b> exhibited the most potent antiviral activity (100% inhibition and TC<sub>50</sub> = 61 μg/μL), comparable to the reference drug amantadine (TC<sub>50</sub> = 72 μg/μL, 100% inhibition). Furthermore, the molecular docking disclosed that the analogues exhibited a range of interactions, such as H-bonding and π-π stacking, with binding affinities between −4.8558 and − 8.3673 kcal/mol. Additionally, the SwissADME predictions indicated that the synthesized analogues possess promising drug-like characteristics, but analogues <b>4a–d</b> and <b>8c</b> demonstrated inadequate solubility and bioavailability, which restricts their use as viable oral medications.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

The Nature of Nanodisc Lipids Influences Fragment-Based Drug Discovery Results

IF 3.2 4区医学

Chemical Biology & Drug Design Pub Date : 2025-03-14 DOI: 10.1111/cbdd.70080

Tim G. J. Knetsch, Henri van Son, Masakazu Kobayashi, Marcellus Ubbink

{"title":"The Nature of Nanodisc Lipids Influences Fragment-Based Drug Discovery Results","authors":"Tim G. J. Knetsch, Henri van Son, Masakazu Kobayashi, Marcellus Ubbink","doi":"10.1111/cbdd.70080","DOIUrl":"https://doi.org/10.1111/cbdd.70080","url":null,"abstract":"<p>Membrane proteins (MPs) are important yet challenging targets for drug discovery. MPs can be reconstituted in protein-lipid Nanodiscs (NDs), which resemble the native membrane environment. Drug-membrane interactions can affect the apparent binding stoichiometry and affinity, as well as the kinetics of ligands for a particular target, which is important for the extrapolation to pharmacokinetic studies. To investigate the role of the membrane, we have applied fragment-based drug discovery (FBDD) methods to cytochrome P450 3A4 (CYP3A4), reconstituted in NDs composed of different phosphocholine lipids: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), or 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC). Surface plasmon resonance screening of fragments and marketed drugs revealed extensive binding to the empty ND, correlating with analyte hydrophobicity, and the binding was critically dependent on ND lipid composition. POPC NDs showed much higher binding of fragments than DMPC and DPhPC NDs, resulting in a lower hit rate for CYP3A4 in POPC NDs, which demonstrated that the choice of the ND lipid is crucial to the outcome of a screen. The number of binders that were rejected based on atypical binding kinetics was lower for monomeric CYP3A4 in NDs than for non-native oligomeric CYP3A4 without the ND. Several fragments were exclusively identified as hits for CYP3A4 in the presence of the ND membrane. It is concluded that the nature of the ND is a critical factor for fragment screening of membrane proteins.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 3","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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