Molecular Diversity最新文献

{"title":"Synthesis of xanthenone fused spiro pyrrolidine oxindoles via multicomponent [3 + 2] cycloaddition reactions.","authors":"Gurusivam Paramasivam, Baskaralingam Palanichamy, Nagaraaj Paramathevar","doi":"10.1007/s11030-025-11167-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11167-w","url":null,"abstract":"<p><p>Xanthenone fused spiro-pyrrolidine oxindoles were conveniently synthesized in good yields with high regio- and diastereoselectivity from a multicomponent synthesis involving tetrahydroxanthenones, α-amino acids, and isatins via an azomethine ylide based [3 + 2] cycloaddition process. We utilized tetrahydroxanthenone as a dipolarophile for the first time in the [3 + 2] cycloaddition of decarboxylated azomethine ylide. The relative configuration of the spirocycloadduct was determined by single-crystal X-ray diffraction analysis.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular insights of vitamin D receptor SNPs and vitamin D analogs: a novel therapeutic avenue for vitiligo.","authors":"Sakthi Sasikala Sundaravel, Beena Briget Kuriakose, Amani Hamad Alhazmi, Sabareeswari Jeyaraman, Sushma Shruthi Jagannathan, Karthikeyan Muthusamy","doi":"10.1007/s11030-025-11168-9","DOIUrl":"https://doi.org/10.1007/s11030-025-11168-9","url":null,"abstract":"<p><p>Vitamin D receptor (VDR) agonists play a pivotal role in modulating immune responses and promoting melanocyte survival, making them potential candidates for vitiligo treatment. The VDR gene is integral to mediating the effects of vitamin D in the immune system, and disruptions in its structure due to missense mutations may significantly contribute to the pathogenesis of vitiligo. Missense single-nucleotide polymorphisms (SNPs) can alter the amino acid sequence of the VDR protein, potentially affecting its ligand-binding affinity and downstream signaling. Investigating these missense SNPs provides critical insights into the genetic underpinnings of vitiligo and may help identify biomarkers for early detection and precision-targeted therapies. This study explored the therapeutic potential of vitamin D analogs in vitiligo management, with a particular focus on their binding interactions and molecular efficacy. Using molecular docking and virtual screening, 24 vitamin D analogs were evaluated. Calcipotriol exhibited the highest binding affinity (-11.4 kcal/mol) and unique interactions with key residues in the VDR ligand-binding domain. Additionally, an analysis of structural variations stemming from missense mutations in the VDR gene highlighted potential impacts on receptor-ligand interactions, further emphasizing the importance of genetic factors in treatment response. These findings underscore the potential of calcipotriol to promote melanogenesis and modulate pigmentation in vitiligo. A comparative analysis identified structural variations influencing the efficacy of other analogs, such as calcitriol and tacalcitol. Although the in silico methods provided valuable insights, the study acknowledges the limitations of excluding dynamic cellular environments and emphasizes the need for experimental validation. Overall, this study enhances our understanding of VDR-targeted therapies, and calcipotriol is a promising candidate for further development in the management of vitiligo.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spiroindoline quinazolinedione derivatives as inhibitors of P-glycoprotein: potential agents for overcoming multidrug resistance in cancer therapy.","authors":"Fatemeh Moosavi, Masoumeh Divar, Soghra Khabnadideh, Marjan Tavakkoli, Maryam Mohabbati, Luciano Saso, Alireza Poustforoosh, Omidreza Firuzi","doi":"10.1007/s11030-025-11150-5","DOIUrl":"https://doi.org/10.1007/s11030-025-11150-5","url":null,"abstract":"<p><p>Multidrug resistance (MDR) presents a major challenge for effectiveness of chemotherapy. This study investigates the effectiveness of spiroindoline quinazolinediones in reversing MDR mediated by P-glycoprotein (P-gp) overexpression in cancer cells. A series of synthesized hybrid spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione derivatives (compounds 5a-5l) were analyzed for their ability to enhance rhodamine 123 (Rhd123) accumulation in the MES-SA/DX5 cell line using flow cytometry. The MTT assay was also employed to evaluate the compounds' effectiveness in reversing drug resistance. Additionally, docking studies and molecular dynamics simulations were conducted to investigate the interaction of these compounds with the P-gp transporter. The Rhd123 accumulation assay in MDR cancer cells revealed that most compounds, in particular 5f, 5g, 5h, 5i, 5j, 5k, and 5l, exhibited significant potential as P-gp inhibitors. Among the tested derivatives, compounds 5g and 5l demonstrated the best effects, and increased Rhd123 accumulation up to 12.9 times compared to untreated cells. Additionally, compounds 5f through 5 l bearing methylbenzyl (5f), benzyl (5g), pentyl (5 ), p-bromobenzyl (5i), p-chlorobenzyl (5j), dichlorobenzyl (5k), and tert-butylbenzyl (5l) substituents on the isatin ring effectively restored sensitivity to doxorubicin at their non-toxic concentrations in resistant MES-SA/DX5 cells. Among these, compound 5l at 5 μM exhibited the highest inhibitory potential, and lowered doxorubicin's IC₅₀ value 10.1 times compared to control. Moreover, in silico investigation identified the potential interactions of test compounds with critical residues of P-gp involved in its efflux function. Our study suggests that the synthesized spiroindoline quinazolinediones may have high potentials as agents capable of reversing MDR in cancer cells.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated AI and machine learning pipeline identifies novel WEE1 kinase inhibitors for targeted cancer therapy.","authors":"Jaikanth Chandrasekaran, Dhanushya Gopal, Lokesh Vishwa Sureshkumar, Infant Xavier Santhiyagu, Varsha Senthil Kumar, Bhuvaneshwari Munuswamy, Beevi Fathima Harshatha Mohamed Yousuf Gani, Mohit Agrawal","doi":"10.1007/s11030-025-11157-y","DOIUrl":"https://doi.org/10.1007/s11030-025-11157-y","url":null,"abstract":"<p><p>The dysregulation of the cell cycle in cancer underscores the therapeutic potential of targeting WEE1 kinase, a key regulator of the G2/M checkpoint. This study harnessed artificial intelligence (AI)-driven methodologies, particularly the MORLD platform, to identify novel WEE1 inhibitors. Starting with clinically validated WEE1 inhibitors as references, we generated 20,000 structurally diverse compounds optimized for binding affinity, synthetic accessibility, and drug-likeness. A rigorous cheminformatics pipeline-comprising PAINS filtering, physicochemical property assessments, and molecular fingerprinting-refined this library to 242 promising candidates. Dimensionality reduction using UMAP and clustering via K-means enabled the prioritization of structurally unique leads. Molecular docking studies highlighted two compounds, MORLD5036 and MORLD6305, with exceptional binding affinities and interactions with key WEE1 active site residues. Molecular dynamics simulations and MM-GBSA binding free energy calculations further validated MORLD5036 as the most stable and potent inhibitor. Scaffold analysis revealed novel chemotypes distinct from existing inhibitors, enhancing potential for intellectual property. Comprehensive ADME profiling confirmed favorable pharmacokinetics, while synthetic accessibility evaluations indicated practicality for experimental validation. The identified lead compound, MORLD5036, exhibits favorable pharmacokinetics and novel chemotypes, positioning it as a potential therapeutic candidate for cancers reliant on WEE1-mediated cell cycle control. This integrated, AI-driven pipeline expedites the identification of next-generation WEE1 inhibitors, paving the way for advancements in precision oncology. Unlike traditional methods reliant on pre-existing datasets, this study leverages MORLD's reinforcement learning framework to autonomously generate inhibitors, enabling exploration of uncharted chemical space. These findings establish MORLD5036 as a computationally promising WEE1 inhibitor candidate warranting further experimental validation.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent progress and structural insights of potential Hsp90 inhibitors as anticancer agents.","authors":"Aastha Singh, Subhadip Maity, Priya Devi, Aman Rai, Vivek Asati","doi":"10.1007/s11030-025-11160-3","DOIUrl":"https://doi.org/10.1007/s11030-025-11160-3","url":null,"abstract":"<p><p>Hsp90, or heat shock protein 90, a well-preserved molecular chaperone that is essential for the coordination of numerous biological pathways and cellular processes. Hsp90 is a molecular chaperone, which promises a target for cancer treatment. Hsp90 inhibitors are a class of drugs that have been extensively studied in preclinical models and demonstrated promise in treating a variety of illnesses, particularly cancer. Hsp90 inhibitors, however, have been encountered a number of challenges during the clinical development process, such as low efficacy, toxicity, and drug resistance. This literature survey emphasizes the importance of HSP90 inhibitors incorporating diverse heterocyclic rings, such as pyrazole, indole, pyrimidine, triazole, and thioquinazoline, which have exhibited promising anticancer activity. This review covers several parameters, including kinetic investigation, binding interactions, IC₅₀ value, structure-activity relationship, and molecular docking studies of the most potent compound. There are several heterocyclic small molecules under investigation in clinical studies, such as AUY922, SNX-5422, STA-9090, and others. This review also contained a patent of HSP90 inhibitors, which showed greater effectiveness. Therefore, the main objective of this paper is to summarize all recent developments in the creation of anticancer medications that target HSP90 inhibitors in order to treat anticancer disease.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug repositioning as a promising approach for the eradication of emerging and re-emerging viral agents.","authors":"Marwa Almulhim, Abdolmajid Ghasemian, Mojtaba Memariani, Farnaz Karami, Asmaa S A Yassen, Athanasios Alexiou, Marios Papadakis, Gaber El-Saber Batiha","doi":"10.1007/s11030-025-11131-8","DOIUrl":"https://doi.org/10.1007/s11030-025-11131-8","url":null,"abstract":"<p><p>The global impact of emerging and re-emerging viral agents during epidemics and pandemics leads to serious health and economic burdens. Among the major emerging or re-emerging viruses include SARS-CoV-2, Ebola virus (EBOV), Monkeypox virus (Mpox), Hepatitis viruses, Zika virus, Avian flu, Influenza virus, Chikungunya virus (CHIKV), Dengue fever virus (DENV), West Nile virus, Rhabdovirus, Sandfly fever virus, Crimean-Congo hemorrhagic fever (CCHF) virus, and Rift Valley fever virus (RVFV). A comprehensive literature search was performed to identify existing studies, clinical trials, and reviews that discuss drug repositioning strategies for the treatment of emerging and re-emerging viral infections using databases, such as PubMed, Scholar Google, Scopus, and Web of Science. By utilizing drug repositioning, pharmaceutical companies can take advantage of a cost-effective, accelerated, and effective strategy, which in turn leads to the discovery of innovative treatment options for patients. In light of antiviral drug resistance and the high costs of developing novel antivirals, drug repositioning holds great promise for more rapid substitution of approved drugs. Main repositioned drugs have included chloroquine, ivermectin, dexamethasone, Baricitinib, tocilizumab, Mab114 (Ebanga™), ZMapp (pharming), Artesunate, imiquimod, saquinavir, capmatinib, naldemedine, Trametinib, statins, celecoxib, naproxen, metformin, ruxolitinib, nitazoxanide, gemcitabine, Dorzolamide, Midodrine, Diltiazem, zinc acetate, suramin, 5-fluorouracil, quinine, minocycline, trifluoperazine, paracetamol, berbamine, Nifedipine, and chlorpromazine. This succinct review will delve into the topic of repositioned drugs that have been utilized to combat emerging and re-emerging viral pathogens.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Quinoline and quinolone carboxamides: A review of anticancer activity with detailed structure-activity relationship analysis.","authors":"Neethu Mariam Thomas, Majed Alharbi, Venkanna Muripiti, Janardhan Banothu","doi":"10.1007/s11030-025-11153-2","DOIUrl":"https://doi.org/10.1007/s11030-025-11153-2","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probing the dark chemical matter against PDE4 for the management of psoriasis using in silico, in vitro and in vivo approach.","authors":"B Swapna, Satvik Kotha, Divakar Selvaraj, Siddamsetty Ramachandra, Aruna Acharya","doi":"10.1007/s11030-025-11159-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11159-w","url":null,"abstract":"<p><p>The potential downsides for the present treatment for psoriasis are drug resistance, reduced efficacy, risk of mental episodes, and drug interactions. Hence, this study aims to discover a new drug for psoriasis by considering global research efforts and exploring underrepresented chemical space regions. The objective was to identify novel PDE4D inhibitors from the dark chemical matter (DCM) database for treating psoriasis. To address this we have coupled molecular docking and pharmacophore screening with molecular dynamics (MD) to identify hit molecules. Additionally, pharmacokinetics optimization was performed using machine learning and artificial intelligence which are key parts of drug discovery and development processes. The 139,353 DCM molecules were evaluated for their binding mode and interaction with critical residues such as GLN369, ILE336, PHE340, and PHE372 of the phosphodiesterase-4D (PDE4D) enzyme. Here, 15 hits were obtained through successive virtual screening procedures and all the 15 molecules were subjected to MD simulations for hit identification. In the MD studies, a stable root mean square deviation (RMSD) and ligand-protein interactions were found with four molecules, namely 027230, 060628, 060576, and 085881. The ligand 085881 was found promising because it inhibits LPS-induced IL-6 and TNF-alpha secretion from THP-1 cells with IC₅₀ of 18.41 μM and 34.43 μM, respectively. In vivo erythema grading showed that 085881 possesses mild to moderate anti-psoriatic action. This study demonstrates the effective use of computational techniques to discover novel PDE4D inhibitors and provides insight into their therapeutic potential for treating inflammatory diseases such as psoriasis.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A practical synthesis of YZD-7082B, a novel orally bioavailable selective estrogen receptor degrader (SERD) for the treatment of ER+ breast cancer.","authors":"Yongqi He, Xin-Yu Leng, Runying Wang, Lulu Sun, Dan Zhang, Yushe Yang","doi":"10.1007/s11030-025-11154-1","DOIUrl":"https://doi.org/10.1007/s11030-025-11154-1","url":null,"abstract":"<p><p>In previous studies, we discovered YZD-7082B, a selective estrogen receptor degrader (SERD) with excellent comprehensive properties. Here, we reported the development of an efficient multigram-scale synthetic process for YZD-7082 in 13 steps. The route featured a chiral resolution of a thiochroman intermediate with a unique cis-1,2-diaryl motif using a chiral amine and a mild reduction of amide using ZnEt₂/LiCl/(EtO)₃SiH system. This approach also overcomes the issues of high loadings of palladium catalysts and long reaction time. The developed process provided YZD-7082B with an HPLC purity of > 99.8% and ee of > 99%.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MedKG: enabling drug discovery through a unified biomedical knowledge graph.","authors":"Madhavi Kumari, Rohit Chauhan, Prabha Garg","doi":"10.1007/s11030-025-11164-z","DOIUrl":"https://doi.org/10.1007/s11030-025-11164-z","url":null,"abstract":"<p><p>Biomedical knowledge graphs have emerged as powerful tools for drug discovery, but existing platforms often suffer from outdated information, limited accessibility, and insufficient integration of complex data. This study presents MedKG, a comprehensive and continuously updated knowledge graph designed to address these challenges in precision medicine and drug discovery. MedKG integrates data from 35 authoritative sources, encompassing 34 node types and 79 relationships. A Continuous Integration/Continuous Update pipeline ensures MedKG remains current, addressing a critical limitation of static knowledge bases. The integration of molecular embeddings enhances semantic analysis capabilities, bridging the gap between chemical structures and biological entities. To demonstrate MedKG's utility, a novel hybrid Relational Graph Convolutional Network for disease-drug link prediction, MedLINK was developed and used in case studies on clinical trial data for disease drug link prediction. Furthermore, a web-based application with user-friendly APIs and visualization tools was built, making MedKG accessible to both technical and non-technical users, which is freely available at http://pitools.niper.ac.in/medkg/.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}