Molecular Diversity最新文献

{"title":"Recent advances in drug repositioning and rediscovery for different therapeutic activities utilizing updated technological approaches.","authors":"Eman S Nossier, Manal M Anwar, Mohamed Ayman El-Zahabi","doi":"10.1007/s11030-025-11248-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11248-w","url":null,"abstract":"<p><p>Traditional or de novo drug discovery is a time-consuming, costly, and high-investment process due to the high attrition rate. Therefore, many trials are conducted to reuse existing drugs to treat pressing conditions and diseases, since their safety profiles and pharmacokinetics are already available. Drug repurposing (DR) (also known as drug repositioning) is a strategy to identify a new indication of existing or already-approved drugs, beyond the scope of their original use. Various in silico-based computational and activity-based experimental approaches to incorporate available resources have been suggested for gaining a better understanding of disease mechanisms and the identification of repurposed drug candidates for personalized pharmacotherapy. This strategy is highly efficient, timesaving, low-cost, and minimum risk of failure. It maximizes the therapeutic value of a drug and consequently increases the success rate. This review introduced publicly available databases for drug repositioning and summarized the approaches taken for drug repositioning. Also, it highlighted and compared their characteristics, which should be addressed for the future realization of drug repositioning.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558768","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":"IUPAC-GPT: an IUPAC-based large-scale molecular pre-trained model for property prediction and molecule generation.","authors":"Jiashun Mao, Tang Sui, Kwang-Hwi Cho, Kyoung Tai No, Jianmin Wang, Dongjing Shan","doi":"10.1007/s11030-025-11280-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11280-w","url":null,"abstract":"<p><p>The international union of pure and applied chemistry (IUPAC) name nomenclature constitutes a universally recognized standard naming system for allocating names to chemical compounds and is a human-friendly, substructure molecular language. Simplified molecular input line entry system (SMILES) string is currently the most popular molecular representation language and is a computer-friendly, atomic-level molecular language. Considering the readability of IUPAC name and the advantages of SMILES string, it becomes significant to investigate the distinctions of these two molecular languages in term of molecular generation and regression/classification tasks. Thus, we have developed a chemical language model named IUPAC-GPT. Besides molecular generation, we have also incorporated the freezing of IUPAC-GPT model parameters and the attachment of trainable lightweight networks for fine-tuning regression/classification tasks. The results indicate that pre-trained IUPAC-GPT can grasp general knowledge that can be effectively transferred to downstream tasks such as molecular generation, binary classification, and property regression prediction. Furthermore, when utilizing the same configuration, IUPAC-GPT exhibited superior performance compared to the smilesGPT model in term of some property prediction tasks. Overall, transformer-like language models pretrained on IUPAC corpora emerge as promising alternatives, offering improved performance in terms of interpretability and semantic abstraction (chemical groups and modifications) when compared to models pretrained on SMILES corpora.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551627","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 repurposing: a promising drug discovery strategy for the treatment of emerging epidemic infectious disease.","authors":"Simeng Zhang, Ruiqing Zhang, Lidan Zheng, Yang Liu, Qing Fan, Yingxu Liu, Xiangzhen Ning, Yanmin Zhang, Yadong Chen, Haichun Liu","doi":"10.1007/s11030-025-11247-x","DOIUrl":"https://doi.org/10.1007/s11030-025-11247-x","url":null,"abstract":"<p><p>Epidemic refers to a disease when the occurrence level exceeds expected standards (generating an epidemic phenomenon), in which infectious diseases pose a major challenge to global health. The concept of epidemiology arises with infectious diseases, which can infect many people within a certain period and lead to a pandemic. Especially in the face of sudden epidemics, time is of the essence. In such urgent scenarios, the time required for traditional drug discovery is often prohibitive, given its inherently long timelines, high costs, and frequent failures. Drug repurposing strategies, mainly divided into experimental and computational approaches,which involves identifying new therapeutic applications for already approved pharmaceuticals, have gained substantial attention as a time-efficient and cost-effective alternative. In light of this, the present review provides a comprehensive overview of the various approaches to drug repurposing for the treatment of emerging epidemic infectious diseases, the majority of which are sudden epidemics caused by viruses. In addition, we discuss the challenges faced by repurposing and propose innovative approaches to address these challenges to better achieve the successful translation of drug repurposing into clinical applications and maximize the therapeutic value of drugs.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551626","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":"Design strategies, structural insights, and biological potential of amyloid-beta inhibitors in Alzheimer's disease.","authors":"Mridul Guleria, Arprita Malhan, Ghanshyam Teli, Nidhi Bisht, Subheet Kumar Jain","doi":"10.1007/s11030-025-11278-4","DOIUrl":"https://doi.org/10.1007/s11030-025-11278-4","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is an insidious neurodegenerative condition characterized by dementia, cognitive decline, and eventual mortality. The pathogenesis of AD is complex, influenced by multiple factors including neurotransmitter deficiencies, particularly acetylcholine (ACh) and the dysregulation of mental homeostasis, reactive oxygen species (ROS), and amyloid-beta (Aβ) peptide accumulation. The latter is firmly linked to the formation of neurofibrillary tangles (NFTs) and amyloid plaques in the cortical and hippocampal regions, which are hallmarks of the disease pathology. Recent advancements in therapeutic strategies have focused on inhibiting the amyloid-beta peptide, a key contributor to AD progression. This study explores the development of novel amyloid-beta inhibitors and their biological activities, focusing on the synthesis of radiolabeled compounds used in the diagnosis and treatment of Alzheimer's disease. Additionally, we explore the roles of crucial enzymes such as Electrophorus electricus acetylcholinesterase (eeAChE), human acetylcholinesterase (hAChE), and human butyrylcholinesterase (hBuChE) in the disease's neurochemical landscape. The goal of this review is to furnish the scientific community with insight into the design of innovative amyloid imaging agents. These agents are based on diverse scaffolds including flavone, pyrimidine, benzimidazole, imidazole, pyridine, pyrrole, quinoline, indanone, acridine, and peptide-based derivatives, serving as core structures for further research and development. This comprehensive evaluation not only elucidates the molecular underpinnings of AD but also propels forward the quest for efficacious diagnostic and therapeutic tools.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551625","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":"Structural characteristics and SARs of EZH2 inhibitors.","authors":"Ruosong Qin, Baohong Ma, Shuo Mou, Mengwen Yuan, Jiahe Xing, Jiwei Shen, Shi Ding, Ye Chen, Ju Liu","doi":"10.1007/s11030-025-11272-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11272-w","url":null,"abstract":"<p><p>Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2 (PRC2), plays a central role in the post-translational methylation of histone H3 lysine 27 (H3K27me3), thereby regulating gene silencing. Extensive studies have demonstrated that EZH2 is frequently overexpressed in a broad range of malignancies, where it promotes tumorigenesis and progression. Elevated EZH2 expression is strongly associated with increased tumor cell proliferation, invasion, metastasis, therapeutic resistance, higher tumor grade, and poor clinical outcomes. Currently, two EZH2 inhibitors have received regulatory approval for the treatment of cancers such as lymphoma, and both have shown clinical benefit in patients with relapsed or refractory disease. In this review, we provided a systematic analysis of recent advances in EZH2 inhibitor development, with a particular emphasis on classification based on core structural scaffolds. We highlighted the structure-activity relationships (SARs), pharmacological profiles, and the respective advantages and limitations of representative compounds in preclinical development. These insights were intended to offer the design of next-generation EZH2 inhibitors with improved selectivity, safety, and translational potential for targeted cancer therapy.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537706","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":"Deciphering the inhibitory mechanisms of Interleukin-17A through dynamic molecular insights: a path toward novel anti-inflammatory therapies.","authors":"Afsheen Razzaq, Madiha Sardar, Mamona Mushtaq, Yan Wang, Mohammad Nur-E-Alam, Zaheer Ul-Haq","doi":"10.1007/s11030-025-11271-x","DOIUrl":"https://doi.org/10.1007/s11030-025-11271-x","url":null,"abstract":"<p><p>IL-17A is a pivotal pro-inflammatory cytokine implicated in a wide spectrum of immunological responses. However, its dysregulation is linked to the progression of various pathological conditions, from mild inflammation to malignant cancers. When IL-17A binds to its cognate receptor, IL-17RA, it forms a complex that initiates a series of molecular signaling cascades within the cell, contributing to various inflammatory processes. Currently, there are no specific oral drugs targeting this pathway, underscoring the urgent need for novel non-inflammatory drugs to address autoimmune and inflammatory diseases. Targeting IL-17A presents a unique opportunity to develop innovative therapies for autoimmune conditions. This research employs ligand-based pharmacophore modeling, followed by screening and docking simulations found six potential drugs that effectively disrupt the IL-17A-IL-17RA combination. Molecular dynamics simulations further demonstrated the stability and inhibitory potential of these compounds, highlighting their interactions within the IL-17A binding site. These interactions involve key residues such as Arg39, Trp51, Trp67, Gln94, Glu95, Leu97, Leu99, Lys114, and Ser118, which are crucial for locking the associated signaling cascade. Mechanistic studies, including dynamic simulations and calculation of free energy, support the efficacy of the identified compounds. Notably, Compounds 1 and 4 exhibit higher binding affinities compared to the native reference inhibitor of target. Our results revealed that both the peptide (Compound 1) and macrocyclic compounds (Compound 3) significantly disrupt the IL-17A/IL-17RA complex, confirming the validity of our approach and reinforcing its potential therapeutic relevance, as highlighted in prior studies. These IL-17A inhibitors show enormous promise as prospective therapeutic candidates for the treatment of inflammatory disorders.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537700","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":"Synthesis, molecular docking, molecular dynamic simulation and biological evaluation of novel 3,4-dihydropyridine derivatives as potent antituberculosis agents.","authors":"Riya Khandelwal, Mahesh Vasava, Vijay Kevlani, Chintan Parmar, Apurva Prajapati, Hitesh Patel, Paresh Patel","doi":"10.1007/s11030-025-11276-6","DOIUrl":"https://doi.org/10.1007/s11030-025-11276-6","url":null,"abstract":"<p><p>Antibiotic resistance is an increasing threat to global public health. Developing new antibiotics and alternative treatments is crucial for combating resistant strains and reducing the global health burden. Hence, we synthesized and evaluated the antitubercular potential of dihydropyridine derivatives. A simplified Biginelli condensation method was employed to synthesize novel 3,4-dihydropyrimidine derivatives (4a-4m) via a one-pot three-component reaction using various substituted benzaldehydes. Reaction completion was monitored via thin-layer chromatography. The structures of the compounds were confirmed by FT-IR, mass spectrometry, ¹H NMR, and ¹³C NMR spectroscopy, and melting points were determined by differential scanning calorimetry. ADMET screening was performed for all synthesized compounds. Selected compounds were tested for their antibacterial and anti-tubercular activity against gram-positive and gram-negative bacteria. ADMET screening identified eight potential compounds: 4c, 4e, 4f, 4g, 4i, 4j, 4k, and 4m. The literature emphasized DprE1 as a critical target for anti-tubercular activity. Molecular docking studies revealed promising binding affinities for compounds 4g (- 7.67), 4d (- 7.316), 4e (- 7.062), and 4c (- 7.042) against DprE1. Furthermore, to study the binding stability and interaction patterns of protein-ligand complexes, a molecular dynamics simulation was performed. The stability of the protein-ligand complex was confirmed by low protein RMSD values and minimal fluctuations in ligand RMSD, indicating a stable binding pose throughout the 200 ns simulation. These compounds also exhibited significant antibacterial activity against gram-positive and gram-negative bacteria compared to standard drugs. In-vitro antitubercular assays against the H37Rv strain demonstrated moderate to notable efficacy relative to the standard reference drug. The findings suggest that these compounds could serve as promising drug candidates. Further development may lead to their use as effective antituberculosis agents in future research.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537707","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":"Oxidative stress and antioxidant therapeutics in autism spectrum disorder: a biochemical and structure-activity relationship perspective.","authors":"Akansha Pal, Falguni Goel, Anushka Sharma, Vipin Kumar Garg","doi":"10.1007/s11030-025-11274-8","DOIUrl":"https://doi.org/10.1007/s11030-025-11274-8","url":null,"abstract":"<p><p>Autism spectrum disorder is a multifaceted neurodevelopmental disorder that involves impaired social interaction, communication challenges, and repetitive behavior. The developing evidence emphasizes a key pathophysiological role for oxidative stress in ASD, which is initiated by an imbalance between ROS generation and antioxidant defense mechanisms. Increased levels of lipid peroxidation, protein oxidation, and DNA damage have been repeatedly found in ASD patients, indicating generalized oxidative damage and mitochondrial impairment. Redox homeostasis disruption is responsible for synaptic dysfunction, neuroinflammation, and disrupted neuronal signaling, worsening the fundamental symptoms of ASD. In this regard, antioxidant therapeutics have attracted a great deal of attention as putative modulators of oxidative stress and neuroinflammation in ASD. Promising candidates such as N-acetylcysteine, glutathione precursors, coenzyme Q10, vitamin E, and polyphenols have been found to be potentially effective against oxidative damage and enhancing behavioral outcomes. The therapeutic potency of such compounds is directly related to their structure-activity relationships, which control their antioxidant activity, bioavailability, and blood-brain barrier permeability. SAR studies have revealed key functional groups, such as thiols, phenolic hydroxyls, and quinone moieties, which increase the free radical scavenging activity and neuroprotective properties of these compounds. In spite of promising preclinical and clinical outcomes, the best dosing, treatment duration, and combinatorial strategies for antioxidant treatments in ASD are poorly characterized. In this review, the biochemical basis of oxidative stress in ASD is examined, the mechanistic understanding of antioxidant-based interventions is assessed, and the structure-activity relationships that dictate their therapeutic value are discussed. Clarifying these molecular complexities will facilitate the development of more potent and targeted antioxidant therapies, bringing new hope for controlling ASD-related oxidative pathologies.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525918","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":"JAK3 identified as a key toxicological target of aristolochic acid in clear cell renal cell carcinoma.","authors":"Jianhang You, Jianmin You, Yuyu Chen, Ronghui Chen, Zhong Lu, Tao Zhao","doi":"10.1007/s11030-025-11268-6","DOIUrl":"https://doi.org/10.1007/s11030-025-11268-6","url":null,"abstract":"<p><p>Aristolochic acid (AA) is a naturally occurring toxin widely present in traditional herbal medicines and is well known for its nephrotoxic and carcinogenic effects. Its association with clear cell renal cell carcinoma (ccRCC) has attracted increasing attention, yet the key molecular targets and underlying mechanisms of AA-induced carcinogenesis remain poorly understood. In this study, 62 intersection genes related to both AA exposure and ccRCC were identified by integrating toxicogenomic databases with ccRCC-associated gene profiles. Transcriptomic analysis and weighted gene co-expression network analysis further narrowed this list to six critical candidates. Diagnostic models built using 13 machine learning algorithms demonstrated robust and consistent performance across multiple datasets. Immune infiltration and functional enrichment analyses suggested that several of these genes may contribute to immune remodeling and metabolic dysregulation. Among them, JAK3 stood out due to its significant upregulation, negative correlation with immunosuppressive cell subsets, and strong association with poor prognosis. Although JAK3 exhibited strong binding affinity to AA in docking analysis, molecular dynamics simulations revealed reduced conformational stability and increased flexibility in its kinase domain, suggesting ligand-induced structural perturbation and potential toxic interference. Collectively, these findings identify JAK3 as a critical toxicological target of AA in ccRCC and demonstrate the power of toxicogenomic and multi-omics integration in uncovering environment-related carcinogenic mechanisms.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525917","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":"Design, synthesis, and in vitro and in vivo anticancer activity of mitochondrial targeted ferulic acid derivatives.","authors":"Yuyu Wu, Ximeng Zhang, Haocheng Li, Xuelian Liu, Jinyao Li","doi":"10.1007/s11030-025-11264-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11264-w","url":null,"abstract":"<p><p>Ferulic acid, a natural active ingredient, mainly exerts antitumor activity by disrupting mitochondrial function and has the advantages of low toxicity and high efficiency. However, poor water solubility and low bioavailability have limited its further development. This article uses triphenylphosphonium salts (TPP⁺) with both amphiphilicity and tumor mitochondrial targeting to modify the structure of ferulic acid, and designs and synthesizes a series of TPP⁺ conjugated ferulic acid derivatives. Compared with ferulic acid, the water solubility, mitochondrial targeting and antitumor activity of TPP-conjugated ferulic acid derivatives were significantly enhanced. Among them, compound I₄ showed excellent anti-cervical cancer activity, mainly by reducing ATP synthesis and promoting ROS production, thus activating mitochondria-mediated apoptotic signaling to induce apoptosis in HeLa cells. I₄ also inhibited HeLa cell migration and caused cell cycle arrest to the G0/G1 phase. In the mouse model, the effective therapeutic concentration of I₄ was 2.5 mg/kg and the LD₅₀ was 98.11 mg/kg. I₄ demonstrated similar anti-cervical cancer activity, a larger therapeutic window and a higher safety profile than with the first-line anticancer agent cisplatin.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525916","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}