Molecular Diversity最新文献

{"title":"Structure-guided discovery of a novel BTK inhibitor inducing apoptosis and G1 phase arrest in tumor cells.","authors":"Alok Shukla, Arpit Sharma, Shivani Gupta, Shruti Raut, Abha Mishra, Siva Hemalatha, Amit Singh","doi":"10.1007/s11030-025-11334-z","DOIUrl":"https://doi.org/10.1007/s11030-025-11334-z","url":null,"abstract":"<p><p>Bruton's tyrosine kinase (BTK) is a pivotal component of multiple signaling pathways in hematopoietic cells and serves as a critical pharmacological target in B-cell malignancies. Despite the availability of clinically approved BTK inhibitors, therapeutic resistance and limited efficacy in certain patient populations necessitate the discovery of novel candidates. In this study, virtual high-throughput screening of the ZINC database was employed to identify potential BTK inhibitors. Compounds were prioritized based on molecular docking scores, binding patterns, and free energy calculations. ZINC000045971961 (ZINC1961) emerged as a promising lead compound, forming stable hydrogen bonds with Glu475 and Met477 key residues also targeted by the reference inhibitor Ibrutinib. Molecular dynamics simulations and MM/GBSA free energy analysis further confirmed the stability and favorable binding affinity of ZINC1961. Biological evaluation in primary tumor cells demonstrated potent cytotoxicity, with an IC₅₀ of 80 ± 0.5 µM, and pronounced apoptosis confirmed by AO/EB/DAPI triple staining, Annexin-V/PI assay, and scanning electron microscopy. Additionally, ZINC1961 induced G1 phase cell cycle arrest, contributing to its antiproliferative effects. Collectively, these findings not only highlight ZINC1961 as a novel BTK inhibitor but also underscore the power of integrative in silico and in vitro approaches in accelerating early-stage cancer drug discovery.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938454","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":"From code to cure: computational identification of LasR inhibitors to combat quorum sensing in P. aeruginosa.","authors":"Subarnarekha Chowdhury, Mukesh Kumar, Shivani Rawat, Shweta Singh, Punit Kaur","doi":"10.1007/s11030-025-11333-0","DOIUrl":"https://doi.org/10.1007/s11030-025-11333-0","url":null,"abstract":"<p><p>Biofilm formation by Pseudomonas aeruginosa (PA) poses a significant challenge in clinical settings due to its contribution to chronic infections and antibiotic resistance. Quorum sensing (QS), particularly regulated by the LasR receptor, plays a crucial role in biofilm development and virulence. In this study, an integrative in silico approach was employed to identify the potential LasR inhibitors. Molecular docking predicted binding affinities of candidate molecules, followed by molecular dynamics simulations to assess complex stability in a dynamic system. Druggability analysis, quantum mechanical evaluation via density functional theory, and binding free energy calculations refined the selection, yielding six promising inhibitors. Among these, compounds 26529, 22498, and 25412 showed strong binding within the LasR-ligand-binding domain, engaging key residues such as Tyr56, Trp60, Asp73, and Ser129. Notably, compound 26529 formed an additional pi-cation interaction with Trp88, providing greater stabilization than typical hydrogen bonds and distinguishing it as the lead molecule. ADMET profiling further confirmed their favorable pharmacokinetic and toxicity properties, selecting the most drug-like candidates. The findings align with the previous reports targeting LasR to attenuate PA virulence and biofilm formation. However, experimental validation remains essential to confirm their therapeutic efficacy. Overall, this study highlights promising QS inhibitors as potential anti-virulence agents against PA.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938417","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":"Mechanistic basis of N-terminal domain-mediated allostery in SIRT6: integrating molecular dynamics simulations and biochemical assays.","authors":"Haiyue Tang, Wenjie Ma, Guoyou Zhang, Jiacheng Wei, Jianyang Ao, Shaoyong Lu","doi":"10.1007/s11030-025-11340-1","DOIUrl":"https://doi.org/10.1007/s11030-025-11340-1","url":null,"abstract":"<p><p>SIRT6, a pivotal member of the NAD⁺-dependent deacetylase superfamily, regulates critical biological processes, including DNA repair, transcriptional regulation, and aging. The deacetylase activity of SIRT6 is allosterically coupled to NAD⁺ binding, enabling site-specific removal of acetyl moieties from lysine substrates. Despite its physiological significance, the structural mechanisms underlying the allosteric regulation mediated by its N-terminal domain (NTD) have remained elusive. In this study, we establish that the NTD of SIRT6 plays an indispensable role in preserving the catalytic geometry by maintaining the NAD⁺ pocket conformation and stabilizing substrate coordination. Molecular dynamics simulations revealed that truncation of the NTD induces an open-state NAD⁺ pocket configuration, accompanied by a reduction in NAD⁺ binding affinity and an increase in the catalytic distance between NAD⁺ and the acetylated lysine substrate. Consistently, enzymatic assays demonstrated a twofold decrease in deacetylation efficiency in NTD-truncated enzyme compared to wild-type SIRT6. These results provide novel mechanistic insights into the NTD-mediated allosteric network essential for SIRT6 catalysis, offering a structural framework for developing modulators targeting this regulatory domain.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938433","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":"Mechanistic inhibition of FtsZ-driven bacterial cytokinesis by natural products: an integrated machine learning and advanced drug discovery approach.","authors":"Rahul Singh, Vishwas Tripathi, Vivek Dhar Dwivedi, Garima Chouhan","doi":"10.1007/s11030-025-11332-1","DOIUrl":"https://doi.org/10.1007/s11030-025-11332-1","url":null,"abstract":"<p><p>Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a major global health burden, particularly due to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. The FtsZ protein, essential for bacterial cytokinesis and lacking a human homolog, presents a selective and non-redundant drug target. In this study, we implemented a comprehensive computational pipeline to identify potential FtsZ inhibitors from the COCONUT natural product database. Initial high-throughput virtual screening and machine learning-based pIC₅₀ prediction were employed to shortlist active compounds. The top candidates were further optimized using Density Functional Theory, followed by ADMET screening, redocking, and 1000-ns molecular dynamics simulations. Binding free energy estimation via MM/GBSA identified CNP0281420 (-53.40 ± 5.57 kcal/mol), CNP0277831 (-50.06 ± 4.19 kcal/mol), and CNP0310586 (-49.47 ± 3.73 kcal/mol) as top binders. These results were supported by QM/MM total energy calculations and PCA-based Free Energy Landscape (FEL) mapping, confirming their conformational stability and electronic compatibility with the FtsZ binding pocket. Overall, this integrative study highlights promising natural compounds with strong binding affinity and dynamic stability, positioning them as potential anti-TB drug candidates for future experimental validation.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938473","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":"AMCF-RDP: a self-attention-based multi-source and cascade framework for the identification of drug-protein relationships.","authors":"Zhanchao Li, Xiaoyu Li, Xiuli Tang, Yan Wang","doi":"10.1007/s11030-025-11337-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11337-w","url":null,"abstract":"<p><p>The identification of relationships between drugs and proteins not only helps in the study of pathological mechanisms but also in drug repositioning studies. However, conventional wet-lab methods are often plagued by issues such as being time-consuming, labour-intensive, and characterized by low accuracy. Therefore, the development of a theoretical computational method is imperative for the expeditious and precise identification of drug-protein relationships. In this study, a self-attention-based multi-source and cascade framework (AMCF-RDP) is developed to identify the drug-protein relationships. Embedded features and network topology features derived from the knowledge graph and complex network were employed to characterize the drug-protein relationships. A two-layer model was constructed using attention mechanism and fully connected layers and was used to predict whether a drug interacts with a protein and what type of interaction it is. The efficacy of the proposed method was evaluated and confirmed based on the non-redundant datasets, ablation experiments, and comparisons with machine learning algorithms and other state-of-the-art methods. Results from fivefold cross-validation demonstrate that the developed method can quickly and accurately recognize drug-protein interactions with an accuracy of 90.21%, a sensitivity of 90.35%, and a Matthews correlation coefficient of 0.8043. Furthermore, it can also distinguish the types of drug-protein interaction, achieving a macro-recall of 93.43% and a macro-F1 score of 0.9381. Compared to the methods described in the literature, the proposed method achieved an area under the receiver operating characteristic curve of 0.9176, representing an improvement of 0.4746. A total of 100,000 drug-protein associations were identified, some of which were confirmed through molecular docking, KEGG, and gene ontology analyses. The AMCF-RDP has been demonstrated to significantly improve the identification of drug-protein relationships. It is anticipated that this will serve as a valuable tool in the domains of drug development and the investigation of mechanisms of action.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938331","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 and synthesis of anti-biofilm derivatives from phospholipid amides.","authors":"Song Bai, Suran Wan, Yi Chen, Miao Li, Rong Wu, Shouying Tang, Lijun Chen, Yazhen Chen, Xiaokang Lv","doi":"10.1007/s11030-025-11270-y","DOIUrl":"https://doi.org/10.1007/s11030-025-11270-y","url":null,"abstract":"<p><p>Bacterial biofilms serve as a natural barrier, enabling bacteria residing within them to exist and potentially amplify bacterial resistance by shielding themselves from bactericide exposure. Despite considerable efforts directed toward inhibiting bacterial growth, research has overlooked bacterial biofilms to a significant extent, leading to the frequent deficiency of traditional antimicrobials in inhibiting such biofilms. This necessitates the development of antimicrobials capable of inhibiting biofilms for effective antibacterial intervention. Herein, we have developed a new bacteriostatic agent, A₆, which has demonstrated the capability of inhibiting biofilm formation. It achieved a biofilm inhibition rate of 72.76% at a concentration of 47.94 μg/mL (2.0 EC₅₀). Mechanistic studies revealed that A₆ inhibits extracellular polymeric substances (EPS) production and bacterial motility, both critical for bacterial virulence, biofilm formation, maturation, or plant cell wall degradation. Additionally, the conductivity and protein leakage experiments demonstrated that compound A₆ significantly affected various physiological processes of Xoc. In summary, A₆ presents a promising antimicrobial solution by simultaneously inhibiting biofilms, addressing a crucial aspect of bacterial plant diseases.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938289","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 metal-free synthesis of phosphoramidates via I^--catalyzed oxidative coupling of anilines/amines with H-phosphonates.","authors":"Mengyu Xie, Huiting Xu, Linjiao Zhu, Tao Cai, Runpu Shen","doi":"10.1007/s11030-025-11327-y","DOIUrl":"https://doi.org/10.1007/s11030-025-11327-y","url":null,"abstract":"<p><p>An efficient and environmentally benign protocol for synthesizing valuable and structurally diverse phosphoramidates via the sodium iodide (NaI)-catalyzed oxidative cross-coupling of various H-phosphonates with both aromatic and aliphatic amines. This new method utilizes H₂O₂ (30% aq.) as a green oxidant, ethyl acetate (EA) as a renewable, low-toxic solvent, and inexpensive, readily available NaI (10 mol%) as the sole catalyst, circumventing the need for toxic reagents, transition metal catalysts, and special equipment. It exhibits excellent compatibility with a wide range of aromatic and aliphatic amines, as well as several amino-containing pharmaceuticals, including Vortioxetine, Fluoxetine, Ceritinib, Linagliptin, and Crizotinib.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938300","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 and preclinical evaluation of an ¹⁸F-labeled 1,5-diarylpyrrole derivative for imaging of COX-2 expression.","authors":"Wenjun Miao, Meixian Yang, Zhiping Peng, Zhu Xia, Xiaoyang Zhang, Yi Chen, Jianhua Jia","doi":"10.1007/s11030-025-11328-x","DOIUrl":"https://doi.org/10.1007/s11030-025-11328-x","url":null,"abstract":"<p><p>Cyclooxygenase-2 (COX-2) plays vital roles in promoting angiogenesis, tissue invasion, and resistance to apoptosis, so it has become an attractive biomarker for imaging and therapy of cancer. Numerous radio-tracers for detection of COX-2 in vivo have been reported, but no one has been successfully applied in clinic. In this study, the radiosynthesis and evaluation of [¹⁸F]6, containing a 1,5-diarylpyrrole structure, as a radiotracer for imaging of COX-2 is described. [¹⁸F]6 was prepared within 90 min synthesis time with radiochemical yields (RCYs) of 2-6% (n = 7, decay corrected) from [¹⁸F]fluoride by a one-step ¹⁸F-trifluoromethylation reaction. After purification by high performance liquid chromatography (HPLC), its radiochemical purity (RCP) was higher than 98%, and the molar activity was 156-210 MBq/mmol. The stability of [¹⁸F]6 was determined by incubation in saline and fetal bovine serum (FBS) in vitro, showing excellent stability in 4 h. The specific binding of [¹⁸F]6 was evaluated using MCF-7 cells (COX-2 positive cells) in vitro, where the radiotracer uptake was blocked in the presence of Celecoxib (a commonly used COX-2 inhibitor). However, no tumor accumulation of [¹⁸F]6 could be observed by micro-PET/CT studies on MCF-7 tumor-bearing mice in vivo. This may be due to the insufficient molar activity of [¹⁸F]6, or inadequate expression of COX-2 in MCF-7. In conclusion, optimizations of radiosynthesis and evaluations of specific binding in suitable model are further still needed to verify the potential of [¹⁸F]6 as a COX-2 imaging agent.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938446","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":"Antimicrobial quinoline triazoles: synthesis, docking, and dynamic simulation studies against biofilm-associated infections.","authors":"Manikandan Sankaran, Kiruthiga Kaliyamoorthy, Manikandan Alagumuthu","doi":"10.1007/s11030-025-11324-1","DOIUrl":"https://doi.org/10.1007/s11030-025-11324-1","url":null,"abstract":"<p><p>The alarming rise of multidrug-resistant (MDR) bacterial pathogens poses a significant challenge to current antimicrobial therapy, challenging the development of novel, structurally diverse agents. In this study, a new series of phenylquinoline-triazoles (PQTs) 4a-l was rationally designed and synthesized using a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry approach. Synthesized PQTs were characterized by standard analytical techniques, including ¹H NMR, ¹³C NMR, HRMS, and spectroscopic analyses. The antimicrobial efficacy of PQTs 4a-l was evaluated against a panel of clinically relevant biofilm-causing bacterial strains, including Streptococcus pneumoniae (MTCC 1936), Staphylococcus aureus (MTCC 737), Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and methicillin-resistant Staphylococcus aureus (MRSA). Candida albicans was the only fungal strain utilized, considering its role in biofilm formation in several infections, including UTI (Urinary Tract Infection). In the results, three PQTs exhibited potent broad-spectrum antibacterial activity, predominantly against Gram-positive strains and MRSA. Due to the activity selectivity, a molecular docking study was executed against the penicillin-binding protein 2a (PBP2a), a key resistance factor in MRSA (PDB ID: 6H5O), and the best compounds screened were subjected to test the PBP2a inhibition potential in vitro. The most active compounds exhibited strong binding affinities and favorable interaction forms within the active site of PBP2a, including hydrogen bonding and π-π stacking with key amino acid residues. Furthermore, the docked complexes were subjected to 100 ns molecular dynamics (MD) simulations, which confirmed their structural stability and robust interactions under physiological conditions. Furthermore, in silico ADME and drug-likeness profiling suggested good pharmacokinetic properties. In conclusion, we identified compounds 4d, 4i, and 4 k as are most effective PQTs among 4a-l with remarkable antimicrobial potentials. These findings determine that PQTs are promising scaffolds for combating resistant bacterial infections such as MRSA and warrant further preclinical investigation.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938286","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":"Effective virtual screening strategy toward JAK3 covalent inhibitors: combining multi‑conformational consensus calculation with covalent docking.","authors":"Jingyu Zhu, Genhong Qiu, Lei Xu, Yanfei Cai, Yun Chen, Jian Jin","doi":"10.1007/s11030-025-11329-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11329-w","url":null,"abstract":"<p><p>Accumulating studies have demonstrated that the overactivation of Janus kinase 3 (JAK3) is closely associated with various inflammatory diseases, establishing it as a potential drug target for the treatment of autoimmune and inflammatory disorders. However, the high homology among kinase structures results in poor selectivity for existing JAK3 inhibitors. The approval of the JAK3 covalent inhibitor ritlecitinib has positioned the development of covalent inhibitors as an effective strategy for enhancing JAK3 selectivity. In this study, we developed a hierarchical virtual screening cascade that includes conventional non-covalent approaches and covalent docking steps to identify novel JAK3 covalent inhibitors. First, consensus scoring-based virtual screening was performed by combining the receptor-ligand pharmacophore model with non-covalent molecular docking to pre-screen suitable non-covalently binding conformations and calculate binding energy. Subsequently, covalent molecular docking was conducted to identify molecules that can form covalent bonds with CYS909 in JAK3. This method was validated for its high accuracy while maintaining efficiency. Finally, this virtual screening strategy was employed to screen the SPECS database, resulting in the identification of several compounds with significant potential as covalent JAK3 inhibitors.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938476","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}