Molecular Diversity最新文献

{"title":"New pyrazole-based derivatives targeting MmpL3 transporter in Mycobacterium tuberculosis: design, synthesis, biological evaluation and molecular docking studies.","authors":"Sarvan Maddipatla, Puja Kumari Agnivesh, Bulti Bakchi, Srinivas Nanduri, Nitin Pal Kalia, Venkata Madhavi Yaddanapudi","doi":"10.1007/s11030-025-11152-3","DOIUrl":"https://doi.org/10.1007/s11030-025-11152-3","url":null,"abstract":"<p><p>This study addresses the urgent need for new drugs to combat multi-drug-resistant tuberculosis (MDR-TB). Focusing on MmpL3, a protein essential for mycobacterial cell wall synthesis, we designed and synthesised 50 new pyrazole-based amide derivatives. These compounds were then tested for their ability to inhibit the growth of various Mycobacterium tuberculosis (Mtb) strains, including both drug-susceptible and drug-resistant strains (resistant to isoniazid, rifampicin, or both). Two compounds, 15 and 35, emerged as potent inhibitors. They showed strong activity against both drug-susceptible and drug-resistant Mtb strains, with low minimum inhibitory concentration (MIC) values of 2 µg/mL and 2-4 µg/mL, respectively. Importantly, these compounds also demonstrated a high selectivity index, meaning they were significantly more toxic to Mtb cells than to human liver cells (HepG2). Compound 15 further proved to be bactericidal, effectively killing Mtb within six days. Interestingly, compounds 15 and 35 were inactive against lab-generated Mtb strains resistant to SQ109, a known MmpL3 inhibitor. This finding, supported by molecular docking, molecular dynamics simulations, and genetic analysis of the mmpl3 gene in the SQ109-resistant strains, strongly suggests that these novel compounds also target MmpL3. This research highlights the potential of pyrazole-based amides as a promising new class of anti-TB drugs. By targeting MmpL3, these compounds offer a novel mechanism of action to combat drug-resistant TB, potentially leading to improved treatment outcomes.</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":"143630161","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 virtual screening and compound generation targeting H275Y mutation in the neuraminidase gene of oseltamivir-resistant influenza strains.","authors":"Wajihul Hasan Khan, Nida Khan, Manoj Kumar Tembhre, Zubbair Malik, Mairaj Ahmad Ansari, Avinash Mishra","doi":"10.1007/s11030-025-11163-0","DOIUrl":"https://doi.org/10.1007/s11030-025-11163-0","url":null,"abstract":"<p><p>Neuraminidase (NA) is an essential enzyme located at the outer layer of the influenza virus and plays a key role in the release of virions from infected cells. The rising incidence of global epidemics has made the urgent need for effective antiviral medications an urgent public health priority. Furthermore, the emergence of resistance caused by specific mutations in the influenza viral genome exacerbates the challenges of antiviral therapy. In view of this, this study aims to identify and analyse possible inhibitors of NA from different subtypes of influenza viruses. Initially, a thorough search was conducted in the Protein Data Bank (PDB) to gather structures of NA proteins that were attached with oseltamivir, a widely recognized inhibitor of NA. Here, 36 PDB entries were found with NA-oseltamivir complexes which were studied to evaluate the diversity and mutations present in various subtypes. Finally, N1(H1N1) protein was selected that demonstrated low IC50 value of oseltamivir with mutation H275Y. In addition, the study utilized BiMODAL generative model to generate 1000 novel molecules with comparable structures to oseltamivir. A QSAR model, based on machine learning (ML), was built utilizing the ChEMBL database to improve the selection process of candidate inhibitors. These inhibitors were subsequently analysed by molecular docking and further the best hits compounds (compound_375, compound_106 and compound_597) were appended to make a bigger molecule (compound_106-375, compound_106-597, and compound_375-597) to fit into the binding pocket of protein. Further, triplicate molecular dynamics simulations lasting 100 ns to assess their effectiveness and binding stability showed that compound_106-375 had the most stable binding with the protein. Key residues, including Asn146, Ala138, and Tyr155, form critical interactions with the ligand, contributing to its stability. The investigation was enhanced by employing principal component analysis (PCA), free energy landscape (FEL), and binding free energy calculations. The total binding free energy (G_TOTAL) of - 169.62 kcal/mol suggests that the contact between compound_106-375 and the mutant N1 (H1N1) protein is thermodynamically favourable. This approach allowed for a thorough comprehension of the binding interactions and possible effectiveness of the discovered inhibitors. Overall, these findings demonstrate that compound_106-375 exhibits favourable binding characteristics and stability. Further experimental validation is required to confirm its efficacy against the H275Y mutant neuraminidase protein and its potential to overcome influenza drug resistance. However, compound_106-375 is suggested as a promising candidate for further development as a therapeutic agent against the mutant N1 (H1N1) protein. This finding will assist in drug development and to overcome the challenges associated with drug resistance in influenza strains.</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":"143630159","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: 1-Styryl-1,3-diketones in the synthesis of spiro[oxindole-3,2'-pyrrolidines] with notable anticancer activity.","authors":"Nikolay S Zimnitskiy, Vladislav Y Korotaev, Maria V Ulitko, Vyacheslav Y Sosnovskikh","doi":"10.1007/s11030-025-11146-1","DOIUrl":"https://doi.org/10.1007/s11030-025-11146-1","url":null,"abstract":"","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":"143630156","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":"Exploiting the Achilles' heel of cancer through a structure-based drug-repurposing approach and experimental validation of top drugs using the TRAP assay.","authors":"Divpreet Kaur, Madhu Chopra, Daman Saluja","doi":"10.1007/s11030-025-11162-1","DOIUrl":"https://doi.org/10.1007/s11030-025-11162-1","url":null,"abstract":"<p><p>Telomerase, a reverse transcriptase implicated in replicative immortality of cancers, remains a challenging target for therapeutic intervention due to its structural complexity and the absence of clinically approved small-molecule inhibitors. In this study, we explored drug repurposing as a pragmatic approach to address this gap, leveraging FDA-approved drugs to accelerate the identification of potential telomerase inhibitors. Using a structure-based drug discovery framework, we screened the DrugBank database through a previously validated pharmacophore model for the FVYL pocket in the hTERT thumb domain, the established binding site of BIBR1532. This was followed by molecular docking, pharmacokinetic filtering, and molecular dynamics (MD) simulations to evaluate the stability of protein-ligand complexes. Binding free energy calculations (MM-PBSA and MM-GBSA) were employed for cross-validation, identifying five promising candidates. Experimental validation using the Telomerase Repeat Amplification Protocol (TRAP) assay confirmed the inhibitory potential of Raltitrexed, showing significant inhibition with IC₅₀ 8.899 µM in comparison to control. Decomposition analysis and Structure-Activity Relationship (SAR) studies further offered insights into the binding mechanism, reinforcing the utility of the FVYL pocket as a druggable site. Raltitrexed's dual mechanism of action, targeting both telomerase and thymidylate synthase, underscores its potential as a versatile anticancer agent, suitable for combination therapies or standalone treatment. As the top lead, Raltitrexed demonstrates the potential of repurposed drugs in telomerase-targeted therapies, offering a time and cost-effective strategy for advancing its clinical development. The study also provides a robust framework for future drug development, addressing challenges in targeting telomerase for anticancer therapy.</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":"143633308","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":"An update on current type 2 diabetes mellitus (T2DM) druggable targets and drugs targeting them.","authors":"Prerna Uniyal, Surbhi Panwar, Akanksha Bhatt, Arockia Babu Marianesan, Roshan Kumar, Thakur Gurjeet Singh, Yogita Tyagi, Ganesh Bushi, Abhay M Gaidhane, Bhupinder Kumar","doi":"10.1007/s11030-025-11149-y","DOIUrl":"https://doi.org/10.1007/s11030-025-11149-y","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia and affects millions of people globally. Even after advancement and development in medical science, it is a big task to achieve victory over type 2 diabetes mellitus (T2DM). T2DM can be a reason for fatal events like stroke, cardiac failure, nephropathy, and retinopathy. Many advanced antidiabetic drugs have been introduced in the market in the past two decades, leading researchers to hunt for new target proteins and their potential modulators that can help develop newer antidiabetic drugs. This review article comprises a broad literature of the latest developments in the management of T2DM concerning new target proteins, their inhibitors, or drugs from the clinical arena employed for the successful management of symptoms of T2DM using mono, dual, or triple combination medication therapy. The review categorizes antidiabetic drugs into three general classes that include conventional drug targets, currently explored targets, and upcoming emerging targets. The review aims to merge information on the medicines affecting these targets, their mechanisms, followed by the chemical structures, and recent advancements.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622922","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":"Multiple pyrazolyazoindole/indazoles scaffolds-based visible-light photoswitches with versatile controlled photophysical properties.","authors":"Haoran Hu, Siyi Wei, Chong Zhang, Chao Gao, Chengguo Sun, Yang Du, Bingcheng Hu","doi":"10.1007/s11030-025-11161-2","DOIUrl":"https://doi.org/10.1007/s11030-025-11161-2","url":null,"abstract":"<p><p>Azoheteroarenes-based photoswitches with high bidirectional isomerization and long thermal half-life (t_1/2) have attracted widespread attention from researchers. The diversity of molecular scaffolds has a profound impact on photoswitching performance, herein, we incorporated dynamic connection sites and scaffold optimization to construct a series of pyrazolyazoindole/indazoles (PAIs)-based photoswitches with adjustable photoswitching properties and versatile photophysical properties upon the irradiation of special wavelength, among them 4Z-H can be switched between states \"lock\" and \"unlock\" by Cu²⁺ ion and EDTA. Thermal stability of series 3Z and 4Z was more stable than other PAIs photoswitches for their intramolecular forces, while the steric effect weakened the thermal stability of series 5D, these results clarified the relationship between the PAIs scaffolds and their photoswitching properties. More importantly, ionic photoswitches (4D-N⁺) synthesized by modification of quaternary ammonium salt fragment exhibited excellent reversible photoswitching properties in aqueous solution with alkaline condition and concentrated glutathione (GSH). The assembly of fluorescence group (triphenylamine) endowed the PAIs scaffolds with optically controlled fluorescence properties. This research elucidated the relationship of scaffold-modification-function of PAIs and would inevitably provide a reliable foundation for the development of intelligent organic materials with photoswitching systems.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622925","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":"Computational modelling of a multiepitope vaccine targeting glycoprotein-D for herpes simplex virus 2 (HSV-2): an immunoinformatic analysis.","authors":"Mohd Sultan Khan, Madhvi Shakya, Chandan Kumar Verma","doi":"10.1007/s11030-025-11148-z","DOIUrl":"https://doi.org/10.1007/s11030-025-11148-z","url":null,"abstract":"<p><p>Herpes Simplex Virus 2 (HSV-2) infection is a global concern, affecting around 500 million individuals worldwide and being the leading cause of genital ulcers. Although several HSV vaccine candidates have been tested in humans, as of right now, neither HSV type has a licenced vaccination available. This study utilized reverse vaccinology to conduct an extensive analysis of the entire genome of HSV-2 where glycoprotein-D was chosen for T-cell epitope predictions. Through an immunoinformatic approach, we identified 2 novel CD8 + and 8 CD4 + T-cell epitopes overlapped within conformational B-cell epitopes, which hold promise as potent vaccine candidates. These epitopes were highly immunogenic and non-toxic, and also showed significant population coverage all over the world. Notably, the predicted epitopes demonstrated cross-reactivity with HSV-1, with the majority exhibiting over 80% conservation within glycoprotein-D. In addition, the designed vaccines' physicochemical properties revealed that these vaccines are non-toxic and non-allergenic, exhibited highly antigenic properties and had the potential to interact with immune receptors effectively. Furthermore, molecular docking studies with human immune receptors, specifically TLR2, demonstrated robust interactions, supported by molecular dynamics simulations indicating stable binding and dynamics. Finally, via codon optimization and in silico cloning, the vaccine candidates were successfully expressed in Escherichia coli, demonstrating feasibility for large-scale production. Computational immune response modelling following varied dosages suggested that the immunogenic constructs could elicit significant immune responses. In conclusion, this study presents promising vaccine candidates against HSV-2, utilizing a rational design approach. However, experimental validation is necessary before advancing to clinical trials.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584269","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":"An innovative approach to development of new pyrazolylquinolin-2-one hybrids as dual EGFR and BRAF^V600E inhibitors.","authors":"Mohamed M Hawwas, Ahmed S Mancy, Mohamed Ramadan, Tarek S Ibrahim, Ashraf H Bayoumi, Mohamed Alswah","doi":"10.1007/s11030-025-11127-4","DOIUrl":"10.1007/s11030-025-11127-4","url":null,"abstract":"<p><p>Novel quinoline-based derivatives 2a-e and 4a-j have been designed and synthesized as potential antiproliferative agents. The designed compounds were screened for their antiproliferative activity against sixty cell lines according to NCI protocol. The promising hybrids 4d-g are screened by MTT assays on three cancer cell lines: leukemia (MOLT-4), lung cancer (HOP-92), and breast cancer (T47D), with IC₅₀ values ranging from 4.982 ± 0.2 to 36.52 ± 1.46 µM compared to Staurosporine, with compound 4e being the most effective. Derivatives 4d-g were evaluated for their inhibitory activity on EGFR and BRAF^V600E. Compound 4e exhibited the highest inhibitory activities, with IC₅₀ values of 0.055 ± 0.002 μM for EGFR and 0.068 ± 0.003 μM for BRAF^V600E, compared to the reference drugs erlotinib (IC₅₀ 0.06 ± 0.002 μM) and vemurafenib (IC₅₀ 0.035 ± 0.001 μM), respectively. Cell cycle analysis of the HOP-92 manifested that pre-G1 apoptosis signaling took place after 4e treatment. Docking simulations were employed to analyze the modes and scores of compounds 4d-g with respect to EGFR and BRAF^V600E. The results revealed that compound 4e exhibited strong affinity for both EGFR and BRAF^V600E compared to the reference drugs with values of - 3.226 and - 3.474 kcal/mol, respectively.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582154","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":"Machine learning-based activity prediction of phenoxy-imine catalysts and its structure-activity relationship study.","authors":"Xiaoke Zhou, Sisi He, Min Xiao, Jing He, Yuan Wang, Yuanqin Zhu, Haixiang He","doi":"10.1007/s11030-025-11147-0","DOIUrl":"https://doi.org/10.1007/s11030-025-11147-0","url":null,"abstract":"<p><p>This study systematically investigates the structure-activity relationships of 30 Ti-phenoxy-imine (FI-Ti) catalysts using machine learning (ML) approaches. Among the tested algorithms, XGBoost demonstrated superior predictive performance, achieving R² values of 0.998 (training set) and 0.859 (test set), with a cross-validated Q² of 0.617. Feature importance analysis identified three composite descriptors-ODI_HOMO_1_Neg_Average GGI2, ALIEmax GATS8d, and Mol_Size_L-as critical contributors, collectively accounting for > 63% of the model's predictive power. Polynomial feature expansion effectively captured nonlinear interactions between descriptors, while SHAP and ICE analyses enhanced interpretability, revealing threshold effects and descriptor-specific trends. However, the model's generalizability may be constrained by the limited dataset size (30 samples) and reliance on density functional theory (DFT)-derived descriptors, necessitating experimental validation. Additionally, the study focused solely on ethylene polymerization at 40 °C; broader applicability to diverse catalytic systems or reaction conditions requires further validation. These findings provide a data-driven framework for catalyst design, though future work should integrate experimental validation and expand datasets to refine predictive robustness.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584271","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":"Development of novel melatonin-isatin hybrids as multifunctional agents for Alzheimer's disease.","authors":"Ying-Ying Zhong, Jun-Ze Deng, Qin Wang, Li Chen, Zi-Hang Yang, Ya-Mei Zhang, Lu-Yi Zhou, Yi-Ran Li, Jia-Qiang Wu, Xiao-Qin Wang","doi":"10.1007/s11030-025-11129-2","DOIUrl":"https://doi.org/10.1007/s11030-025-11129-2","url":null,"abstract":"<p><p>The development of multifunctional agents has been a heated area of research for AD treatment in recent years. In this work, a series of melatonin-isatin hybrids were designed, synthesized, and evaluated as multifunctional agents for treating AD. In vitro studies indicated that most of the synthesized compounds displayed moderate to good MAO-B inhibition activities and good antioxidant activities. In particular, compounds IM-5 and IM-10 exhibited the best inhibitory activities with IC₅₀ value of 12.4 μM and 15.6 μM against MAO-B, and potent antioxidant activities with their ORAC-FL values of 4.6 and 5.2 at 5 μM, respectively. ThT assay revealed compounds IM-5 and IM-10 exhibited the optimal Aβ_1-42 self-induced aggregation inhibitory activities with the inhibition ratio of 72.8% and 69.7% at 20 μM. In addition, compounds IM-5 and IM-10 exhibited low cytotoxicities and significant neuroprotective effects on Aβ_1-42-induced and H₂O₂-induced SH-SY5Y cell injury. More importantly, compounds IM-5 and IM-10 could significantly ameliorate the memory impairment and cognition injury in scopolamine-induced mice. The SwissADME program was used to predict drug-like properties of compounds IM-5 and IM-10 which exhibited they had good pharmacokinetics and drug-likeness properties. Molecular docking study further manifested that compounds IM-5 and IM-10 showed high hMAO-B inhibitory potency. In summary, all above results revealed compounds IM-5 and IM-10 might be promising multifunctional agents for AD treatment.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539885","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}