Molecular Diversity最新文献

{"title":"Design and synthesis of novel indolinone Aurora B kinase inhibitors based on fragment-based drug discovery (FBDD).","authors":"Baoxing Xie, Miaomiao Shi, Dan Tang, Shan Yang, Yan Zeng, Lifei Nie, Chao Niu","doi":"10.1007/s11030-025-11353-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11353-w","url":null,"abstract":"<p><p>Aurora kinases are a group of serine/threonine kinases essential for cell mitosis, comprising Aurora A, B, and C. However, the Aurora B is overexpressed in multiple tumors and the aurone has been proved to exhibit potent inhibitory activity against Aurora B kinase by our group. The indolinone was considered as an aurone scaffold hopping analog, and the indolinone-based Aurora B inhibitor library (3577 molecules) was constructed by FBDD strategy. After pharmacophore model and molecular docking, the candidate molecules were identified, then synthesized via Suzuki-Miyaura and Knoevenagel reactions. The compounds 3-17a, 3-17d and 3-17 k especially inhibited Aurora B in the nanomolar range (IC₅₀ = 1.100, 1.518 and 0.8911 nM, respectively), showing no significant inhibition of Aurora A. Notably, the most potent 3-17 k demonstrated the strongest antiproliferative activity against HGC27 (IC₅₀ = 2.05 μM) and HT-29 (IC₅₀ = 2.07 μM) cell lines, as well as Aurora B over-expression cells, including OVCAR8 (IC₅₀ = 3.02 μM), T24 (IC₅₀ = 10.21 μM), NCIH1299 (IC₅₀ = 7.32 μM) and SW480 (IC₅₀ = 4.45 μM), while maintaining a lower cytotoxicity in normal human cells (GES-1 and NCM460). Additionally, molecular dynamics simulation were conducted to explore the binding interactions between 3-17 k and Aurora B (PDB: 5EYK), revealing favorable binding free energy (-33.34 kcal·mol-1). Based on available data, compound 3-17 k warrants comprehensive investigation to evaluate its potential as an anticancer drug candidate.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028743","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":"Unveiling molecular signatures for precision drug design: machine learning insights from trypanothione reductase, PKC-θ, and CB1.","authors":"Sunil Sahu, Adarsh Anmol, Tushar Nishad, Satya Eswari Jujjavarapu","doi":"10.1007/s11030-025-11287-3","DOIUrl":"https://doi.org/10.1007/s11030-025-11287-3","url":null,"abstract":"<p><p>Traditional drug discovery methods like high-throughput screening and molecular docking are slow and costly. This study introduces a machine learning framework to predict bioactivity (pIC₅₀) and identify key molecular properties and structural features for targeting Trypanothione reductase (TR), Protein kinase C theta (PKC-θ), and Cannabinoid receptor 1 (CB1) using data from the ChEMBL database. Molecular fingerprints, generated via PaDEL-Descriptor and RDKit, encoded structural features as binary vectors. Three models-Random Forest (RF), Gradient Boosting (GB), and a stacking ensemble with Ridge Regression-predicted pIC₅₀, with the ensemble achieving the lowest RMSE. Results highlight heteroatom-containing rings for TR, multiple ring systems for PKC-θ, and aromatic rings for CB1 as critical for high bioactivity. This adaptable framework accelerates drug design by pinpointing optimizable structures, enhancing efficiency in therapeutic development.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028776","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":"Asymmetric Mannich reaction enabled synthesis of alkaloids.","authors":"Summaya Fatima, Asim Mansha, Samreen Gul Khan, Syed Makhdoom Hussain, Bushra Parveen, Ameer Fawad Zahoor, Aqsa Mushtaq, Rabia Ashraf, Aijaz Rasool Chaudhry, Ahmad Irfan","doi":"10.1007/s11030-025-11341-0","DOIUrl":"https://doi.org/10.1007/s11030-025-11341-0","url":null,"abstract":"<p><p>The catalytic asymmetric Mannich reaction is a multicomponent reaction which affords β-amino carbonyl compounds by utilizing an aldehyde, a primary or secondary amine/ammonia, and a ketone. β-amino carbonyl scaffolds are crucial intermediates for the synthesis of naturally occurring bioactive compounds and their derivatives. The synthesized natural compounds exhibit a broad spectrum of biological activities including anti-fungal, anti-cancer, anti-bacterial, anti-HIV, anti-oxidant, and anti-inflammatory activities. Considering the significance of asymmetric Mannich reaction to access diverse biologically active natural products, its applications to afford the synthesis of naturally occurring alkaloids have been summarized here. This review article showcases the key role of asymmetric Mannich reaction in the synthesis of pharmaceutically potent naturally occurring alkaloids, i.e., indole alkaloids, monoterpenoid-indole alkaloids, diterpenoid alkaloids, iso-quinoline alkaloids, polyketide alkaloids, and pyrrolizidine alkaloids, etc., reported since 2015.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022554","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":"9-fluorenone-based synthetic sulfonamide compounds as dual inhibitors of SARS-CoV-2 Main-Protease and Papain-like Protease.","authors":"Sudesna Das, Prasad Sunnapu, Mohammed Rafi, Yasmin Begum, Sudip Dey, Akshay Joshi, Nittu Singh, Krishan Gopal Thakur, Parasuraman Jaisankar, Umesh Prasad Singh","doi":"10.1007/s11030-025-11315-2","DOIUrl":"https://doi.org/10.1007/s11030-025-11315-2","url":null,"abstract":"<p><p>Tilorone, a 9-fluorenone scaffold-based molecule, is a known broad-spectrum antiviral with an IC₅₀ of 180 nM against SARS-CoV-2, but its mechanism is not known. In the present study, we found it to have weak activity against PLpro (IC₅₀ = 30.7 ± 7.5 μM) and was inactive against Mpro. Several sulfonamide derivatives of 9-fluorenone, having the same scaffold as tilorone, were synthesized based on our in-silico studies to enhance their protease activity. They were evaluated for their inhibitory potential for targeting SARS-CoV-2 Mpro (main protease) and PLpro (papain-like protease) using FRET-based high-throughput screening and gel-based assays. Among the derivatives, 3e exhibited dual inhibition against Mpro (IC₅₀ = 23 ± 3.4 μM) and PLpro (IC₅₀ = 6.33 ± 0.5 μM), while 3h selectively inhibited PLpro (IC₅₀= 5.94 ± 1.0 μM). Both 3e and 3h suppressed SARS-CoV-2 replication with IC₅₀ values of 13.4 ± 0.28 μM and 18.2 ± 3.2 μM, respectively. Molecular docking and dynamics studies revealed that the NO₂ group in 3h enhances the rigidity of the BL2 loop of PLpro, contributing to its higher PLpro activity. Both 3e and 3h showed antiviral activity comparable with standard alpha-ketoamide inhibitor (13b-K) in cell-based assays and were non-cytotoxic with acceptable selectivity indices (S.I. > 5.5). These findings suggest that 9-fluorenone-based sulfonamides, particularly 3e and 3h, may be promising candidates as dual or selective protease inhibitors against SARS-CoV-2.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008027","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: A novel ligand-based convolutional neural network for identification of P-glycoprotein ligands in drug discovery.","authors":"Mary Margarat Valentine A Neela, Subbarao Peram","doi":"10.1007/s11030-025-11331-2","DOIUrl":"10.1007/s11030-025-11331-2","url":null,"abstract":"","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022523","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":"Dendrobium officinale Kimura et Migo regulates the proliferation and migration of colon adenocarcinoma via LGALS4.","authors":"Jiawei Miao, Bingrui Luo, Xiuzhen He, Guoli Li, Lu Dou, Yongbo Yan, Xiaoyan Tang","doi":"10.1007/s11030-025-11335-y","DOIUrl":"https://doi.org/10.1007/s11030-025-11335-y","url":null,"abstract":"<p><p>Dendrobium officinale Kimura et Migo (DO) has demonstrated potential anti-colon adenocarcinoma (COAD) effects; however, its underlying mechanisms of action require further elucidation. In this study, DO (work concentrations of 0, 0.1, and 0.01 μg/mL) was administered to HCT116 and Caco-2 cells to evaluated cell viability and migration. Herb databases were utilized to identify potential DO targets. Differential gene screening and weighted gene co-expression network analysis were conducted on the GSE35782 dataset, followed by enrichment analysis and immune infiltration analysis. Key genes were validated using The Cancer Genome Atlas (TCGA), molecular docking, and real-time polymerase chain reaction. The study found that DO significantly inhibited the viability and migration of HCT116 or Caco-2 cells (P < 0.05). A total of 26 key genes were identified, among which galectin-4 (LGALS4) was significantly downregulated in TCGA-COAD (P < 0.05) and was correlated with prognosis (P < 0.05). Molecular docking revealed that the binding energy between LGALS4 and lactose, dendronobiloside A, and dendronobiloside B was-7.22,-9.05, and-8.05 kcal/mol, respectively, forming 5, 11, and 8 hydrogen bonds. Overall, DO effectively suppresses the viability and migration of COAD HCT116 or Caco-2 cells, with LGALS4 potentially serving as a key target.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999445","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":"In silico identification of peptidomimetic inhibitors targeting PXR and RXR interaction to overcome the inactivation of vitamin D in asthma.","authors":"Boutaina Elgharbaoui, E L Mehdi Bouricha, Kaoutar El Guenouni, Meryam Magri, Lahcen Belyamani, Azeddine Ibrahimi, Rachid ELjaoudi, Naima Elhafidi","doi":"10.1007/s11030-025-11336-x","DOIUrl":"https://doi.org/10.1007/s11030-025-11336-x","url":null,"abstract":"<p><p>Asthma is a chronic inflammatory disorder of the airways. Standard treatments, such as inhaled corticosteroids like fluticasone, beclomethasone, and budesonide, are effective in managing asthma symptoms by reducing inflammation through immune suppression. However, prolonged corticosteroid therapy can impair vitamin D metabolism, exacerbating vitamin D deficiency, which is essential for immune regulation and anti-inflammatory responses via the vitamin D receptor (VDR). Activation of the pregnane X receptor (PXR) by corticosteroids induces cytochrome P450 enzyme CYP24A1, accelerating vitamin D catabolism and reducing its anti-inflammatory efficacy. This effect is mediated through the interaction between PXR and its nuclear partner, the retinoid X receptor (RXR), which together regulate gene transcription. Disrupting this PXR-RXR dimerization could offer a selective means to prevent vitamin D degradation without interfering with other physiological functions of PXR or RXR.In this study, we aimed to inhibit the PXR and retinoid X receptor (RXR) interaction by designing peptidomimetic molecules based on the key RXR residues interacting with PXR. To achieve this, we used a multifaceted approach, incorporating pharmacophore and similarity-based peptidomimetics screening, molecular docking, ADMET analysis, and molecular dynamics (MD) simulations. The molecular docking results indicated that 38 compounds had a docking score higher than - 7. Among them, six showed favorable ADMET properties. These molecules were then subjected to MD simulations, where two molecules, notably MMs02510246 and MMs03733211, showed strong interaction with PXR during the 300 ns of MD simulation. Two others partially changed the starting binding site, while two others completely retained their initial binding site and bound to another site. Our study identified two potential molecules that could inhibit the PXR-RXR interaction. These two molecules could potentially inhibit the PXR-RXR interaction, which may help reduce corticosteroid-induced vitamin D inactivation, thereby improving asthma management outcomes without compromising vitamin D's anti-inflammatory benefits. Further experimental analyses are needed to validate our results.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999472","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 insights and activity evaluation of novel SHP-2 inhibitors for targeting type 2 diabetes mellitus.","authors":"Rong Liu, Liang Zou, Maoqi Wang, Yueyue He, Mao Shu","doi":"10.1007/s11030-025-11344-x","DOIUrl":"https://doi.org/10.1007/s11030-025-11344-x","url":null,"abstract":"<p><p>Protein-tyrosine phosphatase-2 (SHP-2) has become a new target in the study of type 2 diabetes mellitus (T2DM). Currently, there are no marketed drugs targeting SHP-2 to study T2DM caused by insulin resistance. Therefore, this study screened out SHP-2 inhibitors with potential inhibitory activity from 2 million compounds, combined with ADME/T, Lipinski &Veber rules, molecular docking and molecular dynamics simulation. It is understood that the mechanism of action to inhibit the activity of SHP-2 protein by compounds is mainly protein amino acid residues PHE-113, GLU-250, LEU-254, GLN-257, PRO-491, and GLN-495 bind to ligands to produce stable conformation. Finally, a series of in vitro preliminary evaluation experiments were conducted to verify the primary activity of the lead compounds. It provides a meaningful reference for the future study of SHP-2 inhibitors with better efficacy, safety, drug-like, bioavailability and drug resistance.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991220","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":"MolMod: a molecular modification platform for molecular property optimization via fragment-based generation.","authors":"Yao Zhou, Zhipei Sang, Chao Xu, Ze Cao, Kaixiang Xiao, Qian Jia, Yutao He, Haibin Luo, Shuheng Huang","doi":"10.1007/s11030-025-11342-z","DOIUrl":"https://doi.org/10.1007/s11030-025-11342-z","url":null,"abstract":"<p><p>Lead optimization is a crucial step in drug design. Generative AI-driven molecular modification has emerged as a powerful strategy to accelerate lead optimization by efficiently exploring chemical space and enhancing key drug-like properties. However, current AI tools primarily focus on de novo scaffold design rather than targeted modifications of validated lead compounds, limiting their practical utility in medicinal chemistry. Herein, we developed MolMod ( http://software.tdd-lab.com/molmod ), a web-based platform that enables site-specific molecular modifications through fragment-based optimization. MolMod employs a transformer model trained on 8.3 million ZINC20 compounds and fine-tuned with ~30,000 medicinal chemistry fragments from ChEMBL. Users mark specific modification sites on their molecules, and the model generates property-optimized fragments for these positions. The platform achieves high scaffold retention while maintaining a ≥99.99% fragment assembly success rate across extensive validation tests. Single-property optimization achieved >93% success rates, while multi-property constraints maintained 95% accuracy. Experimental validation confirmed the platform's accuracy: optimization of α-mangostin increased aqueous solubility from <5 μg/mL to 789 μg/mL through single-site modification, closely matching computational predictions (LogS: -6.128 to -3.829). MolMod provides ADMET profiles for all generated molecules and enables real-time visualization of structural modifications. By focusing on site-specific modifications rather than de novo generation, MolMod aligns with medicinal chemistry workflows and provides a practical tool for both computational and experimental scientists.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991266","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":"Diversity-oriented optimization of 1,2,4-oxadiazole pharmacophore for the discovery of nematicides.","authors":"Yuqin Ou, Qi Zhang, Xue Guo, Ruirui Zhao, Jixiang Chen, Xiuhai Gan","doi":"10.1007/s11030-025-11288-2","DOIUrl":"https://doi.org/10.1007/s11030-025-11288-2","url":null,"abstract":"<p><p>Plant-parasitic nematodes are primary pathogen that cause global crop yield losses, the economic cost to global agriculture is $157 billion a year. With the prohibition of highly toxic chemical nematicides, there are few nematicides available for prevention and control of nematodes. Tioxazafen (3-phenyl-5-thiophen-2-yl-1,2,4-oxadiazole) is a new broad-spectrum nematicide with good control effects against various nematodes. In order to discover new and environmentally friendly chemical nematicides, five series of 43 novel compounds containing 1,2,4-oxadiazole pharmacophore were designed and synthesized by diversity-oriented optimization. The nematocidal activity of the target compounds against Bursaphelenchus xylophilus, Aphelenchoides besseyi and Ditylenchus destructor were systematically evaluated. Bioassay results show that E3((E)-1-(4-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)-N-(4-(trifluoromethyl)phenyl)methanimine) had good nematicidal activity, and its corrected mortality rates were 85.7%, 75.9% and 83.4% to three nematodes at 200 μg/mL, respectively, which was superior to tioxazafen (40.7%, 70.7%, 38.5%). The preliminary mechanisms indicate that compound E3 can inhibit the egg hatching rate, the feeding, and reproductive capabilities of B. xylophilus, and then affect the population of nematodes. In addition, compound E3 can significantly enhance oxidative stress in B. xylophilus. This study revealed that compound E3 has the potential to be a lead candidate for the development of new nematicides.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938390","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}