Bioorganic & Medicinal Chemistry最新文献

{"title":"Discovery of a selective α2C-AR scaffold from a molecular hybridization approach","authors":"Sandip Patra ,&nbsp;Hari K. Namballa ,&nbsp;Ashok R. Gudipally ,&nbsp;Li Xie ,&nbsp;Lei Xie ,&nbsp;Wayne W. Harding","doi":"10.1016/j.bmc.2025.118424","DOIUrl":"10.1016/j.bmc.2025.118424","url":null,"abstract":"<div><div>We undertook the rational design and synthesis of a novel series of ligands intended to function as selective dual dopamine D1 receptor (D1R) partial agonists and D3 receptor (D3R) antagonists. The molecular architecture of these compounds was derived by integrating key pharmacophoric features from established D1R partial agonists and D3R antagonists. Specifically, the 6-(2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione scaffold was employed as the core “tail” region associated with D1R partial agonism, while various substituted phenyl piperazine moieties were introduced as “head” groups to confer D3R antagonistic activity. A pyridine ring was utilized as a central linker across the series.</div><div>Contrary to the intended dopaminergic profile, these compounds exhibited markedly higher binding affinities for α2-adrenergic receptors (α2-ARs) relative to their activity at dopamine receptor subtypes. Several analogues demonstrated potent α2C-AR binding affinities in the low nanomolar range (K_i = 7–30 nM), with moderate selectivity (up to 17-fold) over other α2-AR subtypes. Notably, compounds bearing <em>ortho</em>-substituted aryl groups within the “head” domain generally displayed enhanced α2C-AR binding compared to their <em>para</em>-substituted counterparts.</div><div>Molecular docking studies conducted at both α2A-AR and α2C-AR suggested that multiple receptor-ligand interactions contribute to the observed binding profiles. In particular, an anion–pi interaction between Asp131 of α2C-AR and the phenyl ring of the phenyl piperazine “head” moiety was identified as a possible determinant of the increased α2C-AR affinity observed in <em>ortho</em>-substituted analogues.</div><div>Given the therapeutic potential of selective α2C-AR targeting in treating various disorders, coupled with the limited availability of clinically approved selective α2C-AR ligands, the discovery of this new scaffold offers new prospects for drug discovery targeting α2C-ARs.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118424"},"PeriodicalIF":3.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phthalimide–benzoic acid hybrids as potent aldose reductase inhibitors: Synthesis, enzymatic kinetics, and in silico characterization","authors":"Dafina Hoti ,&nbsp;Arleta Rifati Nixha ,&nbsp;Hatice Esra Duran ,&nbsp;Mustafa Arslan ,&nbsp;Gizem Yıldıztekin ,&nbsp;Abdulilah Ece ,&nbsp;Cüneyt Türkeş","doi":"10.1016/j.bmc.2025.118416","DOIUrl":"10.1016/j.bmc.2025.118416","url":null,"abstract":"<div><div>Aldose reductase (ALR2; AKR1B1) is implicated in hyperglycemia-driven tissue injury and remains a tractable enzymatic target. We developed a concise, chromatography-free two-step route to phthalimide–benzoic acid hybrids (<strong>5a</strong>–<strong>5m</strong>) and profiled their biochemical activity against human ALR2. Across the series, halogenated analogs were most active, with the para-bromophenyl derivative <strong>5d</strong> emerging as the top hit (<em>K</em>_I = 7.56 nM). Steady-state kinetic analysis indicated a competitive inhibition mechanism. Molecular docking to the ALR2 active site (PDB <span><span>4JIR</span><svg><path></path></svg></span>), supported by MM-GBSA rescoring, yielded a catalytically consistent binding mode featuring hydrogen-bonding within the anion-binding region (Tyr48, His110) and complementary hydrophobic contacts (Trp111, Trp219), with Cys298 contributing as a proximal hydrophobic contact. In cell-based assays (A549, Hep3B, L929), the compounds generally showed low intrinsic cytotoxicity at the tested concentrations, suggesting a favorable preliminary safety margin aligned with their ALR2-directed pharmacology. <em>In silico</em> ADME/Tox assessments further supported oral drug-likeness. Overall, these results identify phthalimide–benzoic acid hybrids as tractable ALR2 inhibitor scaffolds that combine potent biochemical inhibition with a competitive kinetic profile and encouraging early safety signals, warranting <em>in vivo</em> evaluation and SAR-guided optimization.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118416"},"PeriodicalIF":3.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research progress on anti-tumor drug resistance of pyridazine-containing structural compounds","authors":"Yu-Lin Liu ,&nbsp;Bing-Qian Li ,&nbsp;Lin-Lin Zhang ,&nbsp;Si-Shuo Chen ,&nbsp;Yi-Po Xi ,&nbsp;Di Zhang ,&nbsp;Hui-Lin Li ,&nbsp;Wen-Juan Zhou ,&nbsp;Li-Ying Ma","doi":"10.1016/j.bmc.2025.118420","DOIUrl":"10.1016/j.bmc.2025.118420","url":null,"abstract":"<div><div>Pyridazine is an aromatic heterocyclic organic compound with a six-membered ring containing four carbon and two nitrogen atoms. Studies have demonstrated their multiple pharmacological properties, including anticancer, antiviral, and anti-Parkinson's disease effects. Recently, there has been increasing interest in their potential anti-tumor resistance activity. Several pyridazine-based drugs and their analogs are currently undergoing clinical trials at different stages, suggesting that pyridazine is a promising chemical structure for drug development. Notably, modifications of pyridazine structures significantly affect their anti-tumor resistance activity. This review summarizes current advances in developing pyridazine derivatives as anti-tumor drug, highlighting key SAR-based design optimization strategies, molecular design principles, and mechanistic insights into target binding. These insights could pave the way for the development of more effective anti-tumor agents overcoming resistance.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118420"},"PeriodicalIF":3.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimization of novel TRPV1 antagonists bearing 1-((2,2-difluorobenzo[d][1,3] dioxol-5-yl) methyl) piperazine for pain management: Mechanistic insights into NLRP3 Inflammasome modulation","authors":"Chunxia Liu ,&nbsp;Ruoyang Miao ,&nbsp;Ning Wang ,&nbsp;Chunli Zhang ,&nbsp;Hai Qian ,&nbsp;Xin Tian","doi":"10.1016/j.bmc.2025.118415","DOIUrl":"10.1016/j.bmc.2025.118415","url":null,"abstract":"<div><div>Emerging evidence underscores the pivotal role of the NLRP3 inflammasome in the pathogenesis of inflammatory pain, positioning it as a promising therapeutic target. Herein, we reported the structure-based design, synthesis, and optimization of novel transient receptor potential vanilloid 1 (TRPV1) antagonist bearing a 1-((2,2-difluorobenzo[d][1,3] dioxol-5-yl) methyl) piperazine scaffold, aiming to simultaneously address TRPV1-mediated neurogenic inflammation and NLRP3-dependent inflammatory signaling. A total of 48 compounds were synthesized and lead compound <strong>3q</strong> demonstrated potent in vitro TRPV1 antagonism (IC₅₀ = 63.1 ± 9.6 nM) and inhibition of NLRP3 inflammasome activation in THP-1 cells, as evidenced by reduced IL-1β secretion (IC₅₀ = 348.9 ± 69.62 nM). In vivo, <strong>3q</strong> significantly alleviated formalin-induced inflammation pain and LPS/ATP-induced acute peritonitis in mice, markedly reducing IL-1β by 51 %. Furthermore, compound <strong>3q</strong> exhibited superior efficacy in DSS-induced colitis, resulting in a lower DAI and histological score. Preliminary pharmacokinetic profiling revealed favorable oral bioavailability (F = 34.4 %) and a half-life of 11.04 h in mice. These findings highlight the potential of <strong>3q</strong> as an alternative anti-inflammatory analgesic, advancing the development of TRPV1/NLRP3 dual modulatory therapies for inflammatory pain management.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118415"},"PeriodicalIF":3.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and SAR studies of N′-(Ethynylsalicylidene)arenecarbohydrazides as next-generation broad-spectrum antifungal agents","authors":"Ashna Garg ,&nbsp;Gabriel S. Matos ,&nbsp;Kathryn Takemura ,&nbsp;Krupanandan Haranahalli ,&nbsp;Shridevi Shrinivasa Bhat ,&nbsp;Nivea Pereira de Sa ,&nbsp;Caroline Mota Fernandes ,&nbsp;Maurizio Del Poeta ,&nbsp;Iwao Ojima","doi":"10.1016/j.bmc.2025.118406","DOIUrl":"10.1016/j.bmc.2025.118406","url":null,"abstract":"<div><div>The present study investigated whether bromine could be replaced with its bioisostere, ethynyl group, without losing potency and selectivity toward fungi, and has found that the bioisosteric replacement strategy is successfully applied to the design, synthesis and SAR study of novel 2nd-generation <em>N</em>′-(salicylidene)arenecarbohydrazides, bearing ethynyl groups. This study particularly focused on the broad-spectrum antifungal activities against three critical priority fungal pathogens, <em>C. neoformans, C. albicans</em>, and <em>A. fumigatus</em> to select highly promising lead compounds. Reliable QSAR models for optimization and further drug development have been successfully created using the AutoQSAR program. Also, in silico ADME/Tox predictions were performed, which predicted considerably improved ClogP values (3.26–5.66), no mutagenicity (AMES test) except for 2 compounds (with low confidence) out of 31, no hERG toxicity, no lethal toxicity (LD₅₀ &gt; 2 Mol/kg), no hepatotoxicity except for 2 compounds out of 31, and good Caco2 permeability. This study has identified 3 compounds, <strong>8.1</strong>, <strong>8.6</strong> and <strong>8.23</strong> as the most promising leads for further drug development, which exhibited excellent broad-spectrum antifungal activities against the three fungal pathogens with high (SI &gt;100) to extremely high (SI up to 17,066) selectivity indices and relevant ClogP values (3.26–4.40). Compounds <strong>8.1</strong> and <strong>8.23</strong> showed synergy in combination with 3 clinical antifungal drugs, especially <strong>8.1</strong> exhibited synergy with 3 clinical drugs against all 3 distinctly different fungal pathogens. Compound <strong>8.23</strong> will serve as the scaffold for developing a new series of bromine-free <em>N</em>′-(salicylidene)arene(or heteroarene)carbohydrazides.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118406"},"PeriodicalIF":3.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, in vitro and in silico anticancer evaluations of novel styryl 1,3,4-oxadiazole-sulfonamide hybrids for colorectal cancer","authors":"Hawkar I. Ahmed ,&nbsp;Onur Can Yazıcı ,&nbsp;Fuad O. Abdullah ,&nbsp;Muhammet Yildirim ,&nbsp;Baram A. Hamah Ameen","doi":"10.1016/j.bmc.2025.118409","DOIUrl":"10.1016/j.bmc.2025.118409","url":null,"abstract":"<div><div>Colorectal cancer (CRC) remains a major contributor to cancer mortality, necessitating novel therapeutic strategies to overcome drug resistance and the adverse effects of current chemotherapeutics. This study aimed to synthesize a new series of styryl-1,3,4-oxadiazole-sulfonamide hybrids and to evaluate their cytotoxicities <em>in vitro</em>, stability of protein-ligand complex, druggability, and solubility properties <em>in silico</em> to find out their potential as an effective anticancer agent for CRC treatment. An efficient multistep approach was used involving a facile reduction of 4-nitrophenyl substituted styryl-1,3,4-oxadiazoles to yield corresponding anilines (<strong>10a-e</strong>), which were subsequently converted into benzenesulfonamides (<strong>11a-o</strong>). All title compounds were obtained in high yields and characterized using FTIR, NMR, and HRMS analysis. The newly synthesized anilines (<strong>10</strong>) and sulfonamides (<strong>11</strong>) were then evaluated for their antiproliferative activities against CRC cell lines, HCT116 and SW48. The results of <em>in vitro</em> studies revealed significant cytotoxic potential of some compounds such as <strong>10a</strong>, <strong>10c</strong>, <strong>11f</strong>, <strong>11</strong><strong>h</strong>, <strong>11i</strong>, and <strong>11</strong><strong>l</strong> showing potent activity (IC₅₀ &lt; 25 μM). In particular, compound <strong>11c</strong> exhibited the strongest activity (IC₅₀: 18.47 μM), which is slightly better than reference drug daunorubicin (IC₅₀: 22.91 μM) against HCT116 cell lines. Furthermore, molecular docking and dynamic simulations studies confirmed the strong interactions between the compounds (<strong>10,11</strong>) and TNIK kinase protein, underpinning their significant anticancer effects. The findings highlight that styryl-1,3,4-oxadiazole aniline derivatives, particularly <strong>11c</strong>, <strong>11f</strong>, <strong>11</strong><strong>h</strong>, <strong>11i</strong>, <strong>11</strong><strong>l</strong>, and <strong>11</strong><strong>m</strong>, may be TNIK-targeted candidate molecules for CRC treatment and show encouraging potential. Further experimental tests against specific TNIK proteins may need to confirm and extend these findings.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118409"},"PeriodicalIF":3.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of inhibitors of the cancer-promoting phosphatase PRL-3 and their evaluation in intestinal organoids","authors":"Andreas Hoffmann ,&nbsp;Judith Weyershaeuser ,&nbsp;Yamini Chand ,&nbsp;Raphael Geißen ,&nbsp;Nico Höfflin ,&nbsp;Birgit Hoeger ,&nbsp;Maja Köhn","doi":"10.1016/j.bmc.2025.118412","DOIUrl":"10.1016/j.bmc.2025.118412","url":null,"abstract":"<div><div>Upregulation of the phosphatase of regenerating liver (PRL)-3 is associated with colorectal cancer as well as metastasis development and progression. PRL-3's overexpression impairs intestinal self-renewal capacity through causing intestinal stem cell death, correlating this cellular mechanism of tumor onset with PRL-3-mediated higher susceptibility to tumor formation upon inflammatory or mutational events. Therefore, PRL-3 inhibitors hold promise as potential therapeutic agents for cancer treatment. Based on the structure of the PRL inhibitor Analog 3, we evaluated here two sets of focused small molecule libraries and screened them in order to identify more potent and selective PRL-3 inhibitors. The best hit, named PRLthiophenib, showed higher inhibition potency <em>in vitro</em> than Analog 3 with improved selectivity for PRL-3 over other protein tyrosine phosphatases (PTPs), but not within the PRL family, which continues to be a challenge. PRLthiophenib presented high cellular stability and no long-term cytotoxicity. Furthermore, it rescued the growth capacity of an inducible PRL-3-expressing three-dimensional intestinal cell culture organoid system derived from a PRL-3 overexpressing mouse line, mimicking the rescue of intestinal self-renewal capacity. The results introduce PRLthiophenib as a complementary inhibitor to published ones and support drug discovery efforts toward therapeutic targeting of this challenging cancer-promoting phosphatase.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118412"},"PeriodicalIF":3.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, biological activity and molecular docking studies of triazolopyridine derivatives as ASK1 inhibitors","authors":"Sheng Su ,&nbsp;Mengyao Peng ,&nbsp;Xiaorui Han ,&nbsp;Xiumei Wang ,&nbsp;Pingping Lan ,&nbsp;Tiantian Wang ,&nbsp;Zengtao Wang","doi":"10.1016/j.bmc.2025.118417","DOIUrl":"10.1016/j.bmc.2025.118417","url":null,"abstract":"<div><div>Apoptosis signal-regulating kinase 1 (ASK1, MAP3K5) is a pivotal mediator in the MAPK pathway, regulating inflammation and fibrosis in Non-alcoholic Steatohepatitis (NASH). A series of novel triazolopyridine derivatives were designed and synthesized as ASK1 inhibitors. Systematic SAR studies identified compound <strong>16a</strong> as a potent inhibitor (IC₅₀ = 149.1 nM). Significantly, <strong>16a</strong> reduced lipid accumulation in LO2 cells, evidenced by decreased Oil Red O-stained lipid droplets and lowered LDL-C, T-CHO, and TG levels in NASH model cells. Mechanistic studies revealed that <strong>16a</strong> suppressed TNF-α-induced activation of the ASK1-p38/JNK signaling pathway in HGC-27 cells and modulated apoptosis-related proteins. These findings highlight <strong>16a</strong> as a promising candidate for anti-NASH therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118417"},"PeriodicalIF":3.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and functional insights into targeting hTERT G-quadruplex by levo-Tetrahydropalmatine in the non-small cell lung cancer","authors":"Huanfeng Ye ,&nbsp;Hong Zhang ,&nbsp;Hong Chen ,&nbsp;Peng Dai ,&nbsp;Yi Wang ,&nbsp;Bingrong Liu ,&nbsp;Yalin Tang","doi":"10.1016/j.bmc.2025.118411","DOIUrl":"10.1016/j.bmc.2025.118411","url":null,"abstract":"<div><div>The G-quadruplex structure in the human telomerase reverse transcriptase (<em>hTERT</em>) promoter has recently emerged as a promising therapeutic target in cancer. However, the development and application are strongly restricted by the lack of selective ligands. Herein, levo-tetrahydropalmatine (l-THP) and its two metabolic derivatives (M1 and M2) were identified as novel ligands of the <em>hTERT</em> G-quadruplex using a combination of fluorescence spectroscopy, UV–visible absorption, circular dichroism (CD), CD-melting assays, electrophoretic mobility shift assays (EMSA), molecular docking, as well as cellular and in vivo models. Our results demonstrate that l-THP, M1, and M2 exhibit potential binding affinity and selectivity toward the <em>hTERT</em> G-quadruplex. Fluorescence mutation assays revealed that these compounds preferentially interact with the junction between the first and second G-tracts (5′-3′), particularly recognizing the cytosine at position 21. Moreover, these ligands significantly suppressed the <em>hTERT</em> mRNA expression (1.00 for control, 0.43 ± 0.02 for l-THP, 0.19 ± 0.01 for M1, 0.33 ± 0.03 for M2) and showed the potent antitumor activity in A549 cells and lung cancer xenograft model. Collectively, these findings establish l-THP and its derivatives as the promising lead compounds for the development of chemotherapeutics against non-small cell lung cancer as well as provide the plausible mechanism insights into potent antitumor activity.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118411"},"PeriodicalIF":3.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based design of novel THR-β agonists and mechanism of activation research by molecular dynamics simulations","authors":"Yang Gao ,&nbsp;Haoran Zhu ,&nbsp;Li-Xin Gao ,&nbsp;Gao-Ya Xu ,&nbsp;Jing Lin ,&nbsp;Lujie Sun ,&nbsp;Wei Li ,&nbsp;Jia Li ,&nbsp;Wei Fu","doi":"10.1016/j.bmc.2025.118397","DOIUrl":"10.1016/j.bmc.2025.118397","url":null,"abstract":"<div><div>Thyroid hormone receptor β (THR-β) plays a crucial role in regulating lipid metabolism, steatohepatitis, and liver fibrosis. The approval of Resmetirom has demonstrated the therapeutic potential of THR-β agonism in treating metabolic-associated steatohepatitis (MASH). Therefore, investigating the mechanism of THR-β activation is essential for understanding its mode of action and further research. In this study, we report a newly designed THR-β agonist, <strong>D4</strong>, which exhibits superior <em>in vitro</em> activity, with a <em>Ki</em> value of 257.3 nM, providing a valuable tool for exploring receptor activation. To gain mechanistic insights, we conducted 500 ns molecular dynamics (MD) simulations on three systems: THR-β bound to agonist <strong>D4</strong>, THR-β bound to a known antagonist <strong>6</strong>, and apo THR-β (ligand-free). A detailed analysis of the structural stability and activation mechanism of these systems was performed. Our findings suggest a novel activation mechanism in which a dynamic salt bridge relay, mediated by Loop-H11-H12, stabilizes the active state of the receptor. In addition, key hydrophobic interaction formed by antagonist and carbon chain of Arg438 was found to be crucial for ligands to switch from agonist to antagonist.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118397"},"PeriodicalIF":3.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}