Pub Date : 2025-01-21DOI: 10.1007/s11030-024-11061-x
Qinghe Hou, Yan Li
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases. Given the multifactorial pathophysiology of AD, monotargeted agents can only alleviate symptoms but not cure AD. Acetylcholinesterase (AChE) and Monoamine oxidase B (MAO-B) are two key targets in the treatment of AD, molecules that inhibiting both targets are considered promising avenue to develop more effective AD therapies. In the present work, a dual inhibition dataset containing 449 molecules was established, based on which five machine learning algorithms (KNN, SVM, RF, GBDT, and LGBM) four fingerprints (MACCS, ECFP4, RDKitFP, PubChemFP) and DRAGON descriptors were combined to develop 25 classification models in which GBDT paired with ECFP4 and RF paired with PubchemFP achieved the same best performance across multiple metrics (Accuracy = 0.92, F1 Score = 0.94, MCC = 0.81). Moreover, based on the curated bioactivity datasets of AChE and MAO-B, regression models were developed to predict pIC50 values. For the AChE inhibition task, GBDT demonstrated the best performance (RMSE = 0.683, MAE = 0.500, R2 = 0.721). The SVM algorithm emerged as the most effective for MAO-B inhibition (RMSE = 0.668, MAE = 0.507, R2 = 0.675). The SHAP algorithm was used to interpret the optimal models, identifying and analyzing the key substructures and properties for both dual-target and single-target inhibitors. Moreover, molecules docking process provided potential mechanism and Structure-Activity Relationships (SAR) of dual-target inhibition further.
阿尔茨海默病(AD)是最常见的神经退行性疾病之一。鉴于阿尔茨海默病的多因素病理生理,单靶向药物只能缓解症状而不能治愈阿尔茨海默病。乙酰胆碱酯酶(AChE)和单胺氧化酶B (MAO-B)是治疗AD的两个关键靶点,抑制这两个靶点的分子被认为是开发更有效的AD治疗方法的有希望的途径。本文建立了包含449个分子的双抑制数据集,在此基础上,结合5种机器学习算法(KNN、SVM、RF、GBDT和LGBM)、4种指纹(MACCS、ECFP4、RDKitFP、PubChemFP)和DRAGON描述符,建立了25个分类模型,其中GBDT与ECFP4配对、RF与PubChemFP配对在多个指标上取得了相同的最佳性能(Accuracy = 0.92, F1 Score = 0.94, MCC = 0.81)。此外,基于整理的AChE和MAO-B生物活性数据集,建立回归模型预测pIC50值。对于AChE抑制任务,GBDT表现最好(RMSE = 0.683, MAE = 0.500, R2 = 0.721)。SVM算法对MAO-B的抑制效果最好(RMSE = 0.668, MAE = 0.507, R2 = 0.675)。利用SHAP算法对优化模型进行解释,识别并分析了双靶点和单靶点抑制剂的关键子结构和性能。此外,分子对接过程进一步提供了双靶点抑制的潜在机制和构效关系。
{"title":"Dual inhibition of AChE and MAO-B in Alzheimer's disease: machine learning approaches and model interpretations.","authors":"Qinghe Hou, Yan Li","doi":"10.1007/s11030-024-11061-x","DOIUrl":"https://doi.org/10.1007/s11030-024-11061-x","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases. Given the multifactorial pathophysiology of AD, monotargeted agents can only alleviate symptoms but not cure AD. Acetylcholinesterase (AChE) and Monoamine oxidase B (MAO-B) are two key targets in the treatment of AD, molecules that inhibiting both targets are considered promising avenue to develop more effective AD therapies. In the present work, a dual inhibition dataset containing 449 molecules was established, based on which five machine learning algorithms (KNN, SVM, RF, GBDT, and LGBM) four fingerprints (MACCS, ECFP4, RDKitFP, PubChemFP) and DRAGON descriptors were combined to develop 25 classification models in which GBDT paired with ECFP4 and RF paired with PubchemFP achieved the same best performance across multiple metrics (Accuracy = 0.92, F1 Score = 0.94, MCC = 0.81). Moreover, based on the curated bioactivity datasets of AChE and MAO-B, regression models were developed to predict pIC<sub>50</sub> values. For the AChE inhibition task, GBDT demonstrated the best performance (RMSE = 0.683, MAE = 0.500, R<sup>2</sup> = 0.721). The SVM algorithm emerged as the most effective for MAO-B inhibition (RMSE = 0.668, MAE = 0.507, R<sup>2</sup> = 0.675). The SHAP algorithm was used to interpret the optimal models, identifying and analyzing the key substructures and properties for both dual-target and single-target inhibitors. Moreover, molecules docking process provided potential mechanism and Structure-Activity Relationships (SAR) of dual-target inhibition further.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998204","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}
The 2-substituted benzimidazole has emerged as a promising heterocyclic compound in the field of drug design. In pursuit of more sustainable photocatalysts for 2-substituted benzimidazole synthesis, the method for coating Fe3O4 with V-doped TiO2 was presented. On the base of characterizing composition, morphology, and properties, the prepared nano-sized Fe3O4@V/TiO2 composites were used as a heterogeneous photocatalyst to catalyze the synthesis of 2-substituted benzimidazoles under light. The photocatalyst Fe3O4@V/TiO2 composites showed the enhanced photocatalytic activity compared to no V-doped Fe3O4@TiO2, being able to yield various 2-substituted benzimidazoles in moderate to good yield with recyclability and stability. A possible photocatalysis mechanism was investigated. It was evident that holes, singlet oxygen, and ·O2̄ radical played important roles in the synthesis of 2-substituted benzimidazole. Moreover, some of the obtained products were demonstrated excellent antibacterial activity.
{"title":"Nano-sized heterogeneous photocatalyst Fe<sub>3</sub>O<sub>4</sub>@V/TiO<sub>2</sub>-catalyzed synthesis and antimycobacterial evaluation of 2-substituted benzimidazoles.","authors":"Lijian Bao, Xiaodong Chen, Yanli Li, Guangyuan Zhu, Jingjun Wang, Mingyue Chen, Xingyu Bian, Qiang Gu, Yumin Zhang, Feng Lin","doi":"10.1007/s11030-024-11085-3","DOIUrl":"https://doi.org/10.1007/s11030-024-11085-3","url":null,"abstract":"<p><p>The 2-substituted benzimidazole has emerged as a promising heterocyclic compound in the field of drug design. In pursuit of more sustainable photocatalysts for 2-substituted benzimidazole synthesis, the method for coating Fe<sub>3</sub>O<sub>4</sub> with V-doped TiO<sub>2</sub> was presented. On the base of characterizing composition, morphology, and properties, the prepared nano-sized Fe<sub>3</sub>O<sub>4</sub>@V/TiO<sub>2</sub> composites were used as a heterogeneous photocatalyst to catalyze the synthesis of 2-substituted benzimidazoles under light. The photocatalyst Fe<sub>3</sub>O<sub>4</sub>@V/TiO<sub>2</sub> composites showed the enhanced photocatalytic activity compared to no V-doped Fe<sub>3</sub>O<sub>4</sub>@TiO<sub>2</sub>, being able to yield various 2-substituted benzimidazoles in moderate to good yield with recyclability and stability. A possible photocatalysis mechanism was investigated. It was evident that holes, singlet oxygen, and ·O<sub>2</sub>̄ radical played important roles in the synthesis of 2-substituted benzimidazole. Moreover, some of the obtained products were demonstrated excellent antibacterial activity.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997823","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}
Pub Date : 2025-01-20DOI: 10.1007/s11030-025-11111-y
Cai-Shi Liu, Jin-Peng Tong, Ze-Yu Fang, Xiao-Meng Guo, Ting-Ting Shi, Shou-Rong Liu, Juan Sun
The quinazoline scaffold serves as a fundamental framework, demonstrating potent anti-tumor activity. Employing the pharmacophore-based scaffold hopping principle, we successfully synthesized a series of FAK/PLK1 inhibitors incorporating the quinazoline scaffold. The synthesized compounds were characterized using 1H NMR, 13C NMR, and HRMS techniques. Through computer-assisted screening and antitumor activity tests, the majority of the compounds demonstrated significant inhibitory effects against various cancer cell lines. Notably, compound 3m exhibited remarkable anticancer activity by inducing G2/M phase cell cycle arrest, apoptosis, as confirmed by western blot assay, cellular fluorescence staining, and transcriptomics testing. Docking simulation was performed to determine the probable binding conformation of compound 3m within the active sites of FAK and PLK1. This compound emerged as a highly promising lead compound during our screening process, displaying high efficiency.
{"title":"Molecular modeling aided design, synthesis and biological evaluation of quinazoline derivatives for the treatment of human cancer.","authors":"Cai-Shi Liu, Jin-Peng Tong, Ze-Yu Fang, Xiao-Meng Guo, Ting-Ting Shi, Shou-Rong Liu, Juan Sun","doi":"10.1007/s11030-025-11111-y","DOIUrl":"https://doi.org/10.1007/s11030-025-11111-y","url":null,"abstract":"<p><p>The quinazoline scaffold serves as a fundamental framework, demonstrating potent anti-tumor activity. Employing the pharmacophore-based scaffold hopping principle, we successfully synthesized a series of FAK/PLK1 inhibitors incorporating the quinazoline scaffold. The synthesized compounds were characterized using <sup>1</sup>H NMR, <sup>13</sup>C NMR, and HRMS techniques. Through computer-assisted screening and antitumor activity tests, the majority of the compounds demonstrated significant inhibitory effects against various cancer cell lines. Notably, compound 3m exhibited remarkable anticancer activity by inducing G2/M phase cell cycle arrest, apoptosis, as confirmed by western blot assay, cellular fluorescence staining, and transcriptomics testing. Docking simulation was performed to determine the probable binding conformation of compound 3m within the active sites of FAK and PLK1. This compound emerged as a highly promising lead compound during our screening process, displaying high efficiency.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997728","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}
Pub Date : 2025-01-20DOI: 10.1007/s11030-024-11037-x
Kapil Laddha, M Elizabeth Sobhia
CD47, a cell surface protein, serves as a "don't eat me" signal that prevents immune cells from engulfing healthy cells upon its interaction with SIRPα. Cancer cells exploit this mechanism by overexpressing CD47 to evade immune destruction. Blocking the interaction between CD47 and its receptor, SIRPα, is a promising therapeutic strategy. Targeting the interactions between these surface proteins with small molecules is quite challenging, and on the other hand, antibodies offer potential. However, the interactions between antigen (CD47) and antibody (B6H12.2) play a crucial role in this scenario, and increasing the affinity by mutating the interacting residues might impact the inclination and effectiveness of the antibody towards antigen. Thus, this study focuses on designing antibodies with increased affinity and stability towards the antigen compared to the wild-type. Residual scanning calculations were performed to mutate the interacting as well as the hydrophobic residues of the antibody and affinity was assessed. Computational approaches, including antigen-antibody docking studies and molecular dynamics simulations, were employed to evaluate the affinity, stability and therapeutic potential of these modified antibodies.
{"title":"Optimizing antibody stability and efficacy in CD47- SIRPα inhibition via computational approaches.","authors":"Kapil Laddha, M Elizabeth Sobhia","doi":"10.1007/s11030-024-11037-x","DOIUrl":"https://doi.org/10.1007/s11030-024-11037-x","url":null,"abstract":"<p><p>CD47, a cell surface protein, serves as a \"don't eat me\" signal that prevents immune cells from engulfing healthy cells upon its interaction with SIRPα. Cancer cells exploit this mechanism by overexpressing CD47 to evade immune destruction. Blocking the interaction between CD47 and its receptor, SIRPα, is a promising therapeutic strategy. Targeting the interactions between these surface proteins with small molecules is quite challenging, and on the other hand, antibodies offer potential. However, the interactions between antigen (CD47) and antibody (B6H12.2) play a crucial role in this scenario, and increasing the affinity by mutating the interacting residues might impact the inclination and effectiveness of the antibody towards antigen. Thus, this study focuses on designing antibodies with increased affinity and stability towards the antigen compared to the wild-type. Residual scanning calculations were performed to mutate the interacting as well as the hydrophobic residues of the antibody and affinity was assessed. Computational approaches, including antigen-antibody docking studies and molecular dynamics simulations, were employed to evaluate the affinity, stability and therapeutic potential of these modified antibodies.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998038","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}
In this paper, a series of oxadiazole/thidiazole containing coumarin derivative derivatives were designed, synthesized and characterized using NMR and HRMS. The evaluation of antiviral activity revealed that some of the synthesized compounds exhibited good in vivo antiviral efficacy against tobacco mosaic virus (TMV). Notably, compounds H6 and Y5 demonstrated exceptional therapeutic and protective effects against TMV, with EC50 values of 180.7, 190.3 and 215.8, 218.6 μg/mL, respectively, surpassing the efficacy of NingNanmycin, which exhibited EC50 values of 284.1 and 247.1 μg/mL. The preliminary mechanistic studies indicated that H6 and Y5 had ahigh binding affinity for the tobacco mosaic virus capsid protein (TMV-CP), potentially obstructing the self-assembly and replication processes of TMV particles. Furthermore, the chlorophyll content and superoxide dismutase (SOD) activity in tobacco leaves increased, while the malondialdehyde (MDA) content decreased. H6 has the potential to be developed as a novel antiviral.
{"title":"Coumarin derivatives containing the 1,3,4 oxadiazole/thiadiazole moiety discovered as potential anti-tobacco mosaic virus agents.","authors":"Yuzhi Hu, Zhiling Sun, Wei Zeng, Yujiao Qiu, Zhiyuan Xu, Jing Zhang, Gang Feng","doi":"10.1007/s11030-024-11098-y","DOIUrl":"https://doi.org/10.1007/s11030-024-11098-y","url":null,"abstract":"<p><p>In this paper, a series of oxadiazole/thidiazole containing coumarin derivative derivatives were designed, synthesized and characterized using NMR and HRMS. The evaluation of antiviral activity revealed that some of the synthesized compounds exhibited good in vivo antiviral efficacy against tobacco mosaic virus (TMV). Notably, compounds H6 and Y5 demonstrated exceptional therapeutic and protective effects against TMV, with EC<sub>50</sub> values of 180.7, 190.3 and 215.8, 218.6 μg/mL, respectively, surpassing the efficacy of NingNanmycin, which exhibited EC<sub>50</sub> values of 284.1 and 247.1 μg/mL. The preliminary mechanistic studies indicated that H6 and Y5 had ahigh binding affinity for the tobacco mosaic virus capsid protein (TMV-CP), potentially obstructing the self-assembly and replication processes of TMV particles. Furthermore, the chlorophyll content and superoxide dismutase (SOD) activity in tobacco leaves increased, while the malondialdehyde (MDA) content decreased. H6 has the potential to be developed as a novel antiviral.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998200","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}
Pub Date : 2025-01-20DOI: 10.1007/s11030-024-11096-0
M Janbozorgi, S Kaveh, M S Neiband, A Mani-Varnosfaderani
Adenosine receptors (A1, A2a, A2b, A3) play critical roles in cellular signaling and are implicated in various physiological and pathological processes, including inflammations and cancer. The main aim of this research was to investigate structure-activity relationships (SAR) to derive models that describe the selectivity and activity of inhibitors targeting Adenosine receptors. Structural information for 16,312 inhibitors was collected from BindingDB and analyzed using machine learning methods. 450 molecular descriptors were calculated for each molecule and compounds were classified based on their activity levels and therapeutic targets. The variable importance in projection (VIP) algorithm identified key discriminating features. Classification models were built using supervised Kohonen networks (SKN) and counter-propagation artificial neural networks (CPANN) algorithms. Model validity was assessed via cross-validation, applicability domain analysis, and test sets. These models were then used to screen a random subset of 2 million molecules from the ZINC database. Three descriptors-hydrophilic factor (Hy), ratio of multiple path count over path count (PCR), and asphericity (ASP)-were identified as critical for discriminating active and inactive inhibitors. SKN models exhibited high sensitivity (0.88-0.99) and yielded an average area under the curve (AUC) of 0.922 for virtual screening. This study aimed to enhance the development of highly selective Adenosine receptor ligands for diverse therapeutic applications by identifying critical molecular features specific to each isoform.
{"title":"General structure-activity relationship models for the inhibitors of Adenosine receptors: A machine learning approach.","authors":"M Janbozorgi, S Kaveh, M S Neiband, A Mani-Varnosfaderani","doi":"10.1007/s11030-024-11096-0","DOIUrl":"https://doi.org/10.1007/s11030-024-11096-0","url":null,"abstract":"<p><p>Adenosine receptors (A<sub>1</sub>, A<sub>2a</sub>, A<sub>2b</sub>, A<sub>3</sub>) play critical roles in cellular signaling and are implicated in various physiological and pathological processes, including inflammations and cancer. The main aim of this research was to investigate structure-activity relationships (SAR) to derive models that describe the selectivity and activity of inhibitors targeting Adenosine receptors. Structural information for 16,312 inhibitors was collected from BindingDB and analyzed using machine learning methods. 450 molecular descriptors were calculated for each molecule and compounds were classified based on their activity levels and therapeutic targets. The variable importance in projection (VIP) algorithm identified key discriminating features. Classification models were built using supervised Kohonen networks (SKN) and counter-propagation artificial neural networks (CPANN) algorithms. Model validity was assessed via cross-validation, applicability domain analysis, and test sets. These models were then used to screen a random subset of 2 million molecules from the ZINC database. Three descriptors-hydrophilic factor (Hy), ratio of multiple path count over path count (PCR), and asphericity (ASP)-were identified as critical for discriminating active and inactive inhibitors. SKN models exhibited high sensitivity (0.88-0.99) and yielded an average area under the curve (AUC) of 0.922 for virtual screening. This study aimed to enhance the development of highly selective Adenosine receptor ligands for diverse therapeutic applications by identifying critical molecular features specific to each isoform.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998221","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}
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, often linked to overexpression or abnormal activation of the epidermal growth factor receptor (EGFR). The issue of developing resistance to third-generation EGFR kinase inhibitors, such as osimertinib, underscores the urgent need for new therapies to overcome this resistance. Our findings revealed that compound A8 exhibits 88.01% kinase inhibition efficacy against the EGFRL858R/T790M mutation at a concentration of 0.1 μM, with an IC50 value of 5.0 nM. Moreover, its selectivity for this double mutation is 29.5, surpassing that of osimertinib. Most notably, A8 demonstrates an inhibitory activity of 2.9 nM against the EGFRL858R/T790M/C797S triple mutation, outperforming the benchmark drug osimertinib. Furthermore, compound A8 has demonstrated strong antiproliferative effects against H1975 cells, and its activity was better than osimertinib. The mechanism by which compound A8 operates as a selective EGFRL858R/T790M inhibitor was confirmed through a series of cell migration, apoptosis, and cell cycle assays. This lays the foundation for the development of a new structural type of EGFR kinase inhibitors.
{"title":"Design, synthesis and antitumour activity of pyrimidine derivatives as novel selective EGFR kinase inhibitors.","authors":"Cheng Zhang, Yiwen Huo, Jianfang Fu, Yue Liu, Qinjiang Zhou, Mingyue Hou, Xiaoxuan Duan, Yanna Lv, Jinxing Hu","doi":"10.1007/s11030-024-11048-8","DOIUrl":"https://doi.org/10.1007/s11030-024-11048-8","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, often linked to overexpression or abnormal activation of the epidermal growth factor receptor (EGFR). The issue of developing resistance to third-generation EGFR kinase inhibitors, such as osimertinib, underscores the urgent need for new therapies to overcome this resistance. Our findings revealed that compound A8 exhibits 88.01% kinase inhibition efficacy against the EGFR<sup>L858R/T790M</sup> mutation at a concentration of 0.1 μM, with an IC<sub>50</sub> value of 5.0 nM. Moreover, its selectivity for this double mutation is 29.5, surpassing that of osimertinib. Most notably, A8 demonstrates an inhibitory activity of 2.9 nM against the EGFR<sup>L858R/T790M/C797S</sup> triple mutation, outperforming the benchmark drug osimertinib. Furthermore, compound A8 has demonstrated strong antiproliferative effects against H1975 cells, and its activity was better than osimertinib. The mechanism by which compound A8 operates as a selective EGFR<sup>L858R/T790M</sup> inhibitor was confirmed through a series of cell migration, apoptosis, and cell cycle assays. This lays the foundation for the development of a new structural type of EGFR kinase inhibitors.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998202","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}
Pub Date : 2025-01-20DOI: 10.1007/s11030-025-11106-9
Zhitian Huang, Qianyu Huang, Hong Wei, Jinzhe Chen, Jiayi Wang, Gonghua Song
Succinate dehydrogenase (SDH) has been identified as one of the ideal targets for the development of novel nematicides. However, the resistance of nematodes to fluopyram, one of the commercialized SDH inhibitors, is becoming a growing concern. Since expanding the structural diversity around an active scaffold is a useful strategy for drug development, herein a series of fluopyram analogues with a broad, biologically relevant indole moiety were synthesized and evaluated for nematicidal activity against C. elegans. Fifty-six novel target compounds were synthesized and characterized by 1H NMR, 13C NMR, and HRMS. The bioscreen results revealed that a few compounds such as C16 and D21 with LC50/72 h values of 8.65 mg/L and 6.83 mg/L, respectively, showed compatible activity to that of the commercial nematicide tioxazafen (LC50/72 h = 5.98 mg/L). Molecular docking indicated that these compounds could effectively bind to the active site of SDH by forming hydrogen bonds with Trp215 and Tyr96, and causing a cation-π interaction with Arg74. The work suggests that indole-containing derivatives may represent a promising template for the development of new nematicides.
琥珀酸脱氢酶(SDH)已被确定为开发新型杀线虫剂的理想靶点之一。然而,线虫对商业化的SDH抑制剂之一氟吡喃(fluopyram)的耐药性日益受到关注。由于扩大活性支架周围的结构多样性是药物开发的有用策略,因此本文合成了一系列具有广泛的生物相关吲哚片段的氟吡喃类似物,并评估了其对秀丽隐杆线虫的杀线虫活性。合成了56个新的目标化合物,并通过1H NMR、13C NMR和HRMS对其进行了表征。生物筛选结果显示,C16和D21的LC50/72 h值分别为8.65 mg/L和6.83 mg/L,与市售杀线虫剂噻沙芬(LC50/72 h = 5.98 mg/L)具有配伍活性。分子对接表明,这些化合物可以通过与Trp215和Tyr96形成氢键,并与Arg74发生阳离子-π相互作用,有效结合SDH的活性位点。这项工作表明,含吲哚衍生物可能为开发新的杀线虫剂提供了一个有希望的模板。
{"title":"Fluopyram analogues containing an indole moiety: synthesis, biological activity and molecular docking study.","authors":"Zhitian Huang, Qianyu Huang, Hong Wei, Jinzhe Chen, Jiayi Wang, Gonghua Song","doi":"10.1007/s11030-025-11106-9","DOIUrl":"https://doi.org/10.1007/s11030-025-11106-9","url":null,"abstract":"<p><p>Succinate dehydrogenase (SDH) has been identified as one of the ideal targets for the development of novel nematicides. However, the resistance of nematodes to fluopyram, one of the commercialized SDH inhibitors, is becoming a growing concern. Since expanding the structural diversity around an active scaffold is a useful strategy for drug development, herein a series of fluopyram analogues with a broad, biologically relevant indole moiety were synthesized and evaluated for nematicidal activity against C. elegans. Fifty-six novel target compounds were synthesized and characterized by <sup>1</sup>H NMR, <sup>13</sup>C NMR, and HRMS. The bioscreen results revealed that a few compounds such as C16 and D21 with LC<sub>50/72 h</sub> values of 8.65 mg/L and 6.83 mg/L, respectively, showed compatible activity to that of the commercial nematicide tioxazafen (LC<sub>50/72 h</sub> = 5.98 mg/L). Molecular docking indicated that these compounds could effectively bind to the active site of SDH by forming hydrogen bonds with Trp215 and Tyr96, and causing a cation-π interaction with Arg74. The work suggests that indole-containing derivatives may represent a promising template for the development of new nematicides.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998207","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}
This study focuses on the design, synthesis, and evaluation of benzimidazole derivatives for their anti-tumor activity against A549 and PC-3 cells. Initial screening using the MTT assay identified compound 5m as the most potent inhibitor of A549 cells with an IC50 of 7.19 μM, which was superior to the positive agents 5-Fluorouracil and Gefitinib. Cellular mechanism studies elucidated 5m arrests cell cycle at G2/M phase, induces apoptosis along with the decrease of mitochondrial membrane potential and increased reactive oxygen species. Colony formation and wound healing assays demonstrated that 5m markedly inhibited the clonogenic and migratory abilities of A549 cells. Western blot analysis showed an upregulation of pro-apoptotic protein Bax, downregulation of anti-apoptotic protein Bcl-2, and significant downregulation of cell cycle proteins CyclinB1 and CDK-1. These findings suggest that compound 5m effectively suppresses A549 cell proliferation and migration through multiple mechanisms, highlighting its potential as a novel anti-lung cancer agent.
{"title":"Design, synthesis, and in vitro antitumor evaluation of novel benzimidazole acylhydrazone derivatives.","authors":"Lihui Shao, Nianlin Feng, Yue Zhou, Chengpeng Li, Danping Chen, Chenchen Li, Xiang Zhou, Zhurui Li, Zhenchao Wang","doi":"10.1007/s11030-024-11064-8","DOIUrl":"https://doi.org/10.1007/s11030-024-11064-8","url":null,"abstract":"<p><p>This study focuses on the design, synthesis, and evaluation of benzimidazole derivatives for their anti-tumor activity against A549 and PC-3 cells. Initial screening using the MTT assay identified compound 5m as the most potent inhibitor of A549 cells with an IC<sub>50</sub> of 7.19 μM, which was superior to the positive agents 5-Fluorouracil and Gefitinib. Cellular mechanism studies elucidated 5m arrests cell cycle at G2/M phase, induces apoptosis along with the decrease of mitochondrial membrane potential and increased reactive oxygen species. Colony formation and wound healing assays demonstrated that 5m markedly inhibited the clonogenic and migratory abilities of A549 cells. Western blot analysis showed an upregulation of pro-apoptotic protein Bax, downregulation of anti-apoptotic protein Bcl-2, and significant downregulation of cell cycle proteins CyclinB1 and CDK-1. These findings suggest that compound 5m effectively suppresses A549 cell proliferation and migration through multiple mechanisms, highlighting its potential as a novel anti-lung cancer agent.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998203","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}
Pub Date : 2025-01-17DOI: 10.1007/s11030-024-11090-6
Cheng Wang, Yi-Ling Wang, Qiu-Han Xu
Parkinson's disease (PD) is a chronic neurodegenerative disorder marked by dopaminergic neuron degeneration in the substantia nigra. Emerging evidence suggests vitamin D3 (VD) plays a therapeutic role in PD, but its precise molecular mechanisms remain unclear. This study employed network pharmacology and bioinformatics to identify VD's hub targets and related pathways. We identified 24 VD's anti-PD targets, with estrogen receptor 1, estrogen receptor 2 (ESR2), sodium-dependent norepinephrine transporter, and insulin-like growth factor 1 receptor emerging as hub targets. Gene enrichment analysis elucidated that VD's anti-PD mechanism is closely related to the estrogen signaling pathway. Additionally, two-sample Mendelian randomization suggested a positive causal relationship between 25-hydroxyvitamin D and estrogen levels in vivo. To verify the interaction between VD and the hub drug targets, we performed molecular docking and kinetic simulations, finding the strongest interaction between VD and ESR2. Further Mendelian randomization analysis of drug targets confirmed the significant effect of the ESR2 drug target on PD risk. Single-cell nuclear sequencing of dopaminergic neurons, coupled with GSEA analysis, indicated that ESR2 activation upregulates the neuroactive ligand-receptor interaction signaling pathway and downregulates the Parkinson's disease pathway, thereby exerting a neuroprotective effect. In summary, our findings suggest that VD supplementation can not only elevate estradiol levels in humans but also directly activate ESR2, thereby modulating the estrogen signaling pathway in PD patients and providing neuroprotection. These predictive biological targets offer promising avenues for future clinical applications in Parkinson's disease treatment.
{"title":"Integrating network pharmacology with molecular docking and dynamics to uncover therapeutic targets and signaling mechanisms of vitamin D3 in Parkinson's disease.","authors":"Cheng Wang, Yi-Ling Wang, Qiu-Han Xu","doi":"10.1007/s11030-024-11090-6","DOIUrl":"https://doi.org/10.1007/s11030-024-11090-6","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a chronic neurodegenerative disorder marked by dopaminergic neuron degeneration in the substantia nigra. Emerging evidence suggests vitamin D3 (VD) plays a therapeutic role in PD, but its precise molecular mechanisms remain unclear. This study employed network pharmacology and bioinformatics to identify VD's hub targets and related pathways. We identified 24 VD's anti-PD targets, with estrogen receptor 1, estrogen receptor 2 (ESR2), sodium-dependent norepinephrine transporter, and insulin-like growth factor 1 receptor emerging as hub targets. Gene enrichment analysis elucidated that VD's anti-PD mechanism is closely related to the estrogen signaling pathway. Additionally, two-sample Mendelian randomization suggested a positive causal relationship between 25-hydroxyvitamin D and estrogen levels in vivo. To verify the interaction between VD and the hub drug targets, we performed molecular docking and kinetic simulations, finding the strongest interaction between VD and ESR2. Further Mendelian randomization analysis of drug targets confirmed the significant effect of the ESR2 drug target on PD risk. Single-cell nuclear sequencing of dopaminergic neurons, coupled with GSEA analysis, indicated that ESR2 activation upregulates the neuroactive ligand-receptor interaction signaling pathway and downregulates the Parkinson's disease pathway, thereby exerting a neuroprotective effect. In summary, our findings suggest that VD supplementation can not only elevate estradiol levels in humans but also directly activate ESR2, thereby modulating the estrogen signaling pathway in PD patients and providing neuroprotection. These predictive biological targets offer promising avenues for future clinical applications in Parkinson's disease treatment.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998222","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}