Molecular Diversity最新文献_第9页

Targeting cyclin-dependent kinase 11: a computational approach for natural anti-cancer compound discovery. 靶向周期蛋白依赖性激酶11：一种发现天然抗癌化合物的计算方法。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-01-23 DOI: 10.1007/s11030-025-11107-8

Suruchi Bhambri, Prakash C Jha

{"title":"Targeting cyclin-dependent kinase 11: a computational approach for natural anti-cancer compound discovery.","authors":"Suruchi Bhambri, Prakash C Jha","doi":"10.1007/s11030-025-11107-8","DOIUrl":"https://doi.org/10.1007/s11030-025-11107-8","url":null,"abstract":"Cancer, a leading global cause of death, presents considerable treatment challenges due to resistance to conventional therapies like chemotherapy and radiotherapy. Cyclin-dependent kinase 11 (CDK11), which plays a pivotal role in cell cycle regulation and transcription, is overexpressed in various cancers and is linked to poor prognosis. This study focused on identifying potential inhibitors of CDK11 using computational drug discovery methods. Techniques such as pharmacophore modeling, virtual screening, molecular docking, ADMET predictions, molecular dynamics simulations, and binding free energy analysis were applied to screen a large natural product database. Three pharmacophore models were validated, leading to the identification of several promising compounds with stronger binding affinities than the reference inhibitor. ADMET profiling indicated favorable drug-like properties, while molecular dynamics simulations confirmed the stability and favorable interactions of top candidates with CDK11. Binding free energy calculations further revealed that UNPD29888 exhibited the strongest binding affinity. In conclusion, the identified compound shows potential as a CDK11 inhibitor based on computational predictions, suggesting their future application in cancer treatment by targeting CDK11. These computational findings encourage further experimental validation as anti-cancer agents.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021604","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}

引用次数: 0

Discovery of selective ROCK2 inhibitors with free radical scavenging ability for the treatment of gouty arthritis. 发现具有自由基清除能力的选择性ROCK2抑制剂治疗痛风性关节炎。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-01-23 DOI: 10.1007/s11030-024-11054-w

Ruolin Cao, Chuqiao Song, Zhe Wang, Bingqing Lv, Wei Xiao, Guoliang Chen, Xuefei Bao

引用次数: 0

Anti-TMV activity based flavonol derivatives containing piperazine sulfonyl: Design, synthesis and mechanism study. 基于抗tmv活性的哌嗪磺酰类黄酮醇衍生物的设计、合成及机理研究。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-01-22 DOI: 10.1007/s11030-025-11109-6

Zhiling Sun, Wei Zeng, Yujiao Qiu, Yuzhi Hu, Qing Zhou, Chunmei Hu, Yuhong Wang, Wei Xue

引用次数: 0

Optimizing kinase and PARP inhibitor combinations through machine learning and in silico approaches for targeted brain cancer therapy. 通过机器学习和计算机方法优化激酶和PARP抑制剂组合用于靶向脑癌治疗。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-01-22 DOI: 10.1007/s11030-025-11114-9

Alireza Poustforoosh

{"title":"Optimizing kinase and PARP inhibitor combinations through machine learning and in silico approaches for targeted brain cancer therapy.","authors":"Alireza Poustforoosh","doi":"10.1007/s11030-025-11114-9","DOIUrl":"https://doi.org/10.1007/s11030-025-11114-9","url":null,"abstract":"The drug combination is an attractive approach for cancer treatment. PARP and kinase inhibitors have recently been explored against cancer cells, but their combination has not been investigated comprehensively. In this study, we used various drug combination databases to build ML models for drug combinations against brain cancer cells. Some decision tree-based models were used for this purpose. The results were further evaluated using molecular docking and molecular dynamics (MD) simulation. The possibility of the hit drug combinations for crossing the Blood-brain barrier (BBB) was also examined. Based on the obtained results, the combination of niraparib, as the PARP inhibitor, and lapatinib, as the kinase inhibitor, exhibited more considerable outcomes with a remarkable model performance (accuracy of 0.915) and prediction confidence of 0.92. The protein tweety homolog 3 and BTB/POZ domain-containing protein 2 are the main targets of niraparib and lapatinib with - 10.2 and - 8.5 scores, respectively. Due to the outcomes, this drug combination can use the CAT1 transporter on the BBB surface and effectively cross the BBB. Based on the obtained results, niraparib-lapatinib can be a promising drug combination candidate for brain cancer treatment. This combination is worth to be examined by experimental investigation in vitro and in vivo.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998058","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}

引用次数: 0

Apigenin-mediated MARK4 inhibition: a novel approach in advancing Alzheimer's disease therapeutics. 芹菜素介导的MARK4抑制：推进阿尔茨海默病治疗的新途径

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-01-22 DOI: 10.1007/s11030-025-11104-x

Afzal Hussain, Deeba Shamim Jairajpuri, Saleha Anwar, Arunabh Choudhury, Mohammed F Hawwal, Anam Firdous, Mohamed F Alajmi, Md Imtaiyaz Hassan

{"title":"Apigenin-mediated MARK4 inhibition: a novel approach in advancing Alzheimer's disease therapeutics.","authors":"Afzal Hussain, Deeba Shamim Jairajpuri, Saleha Anwar, Arunabh Choudhury, Mohammed F Hawwal, Anam Firdous, Mohamed F Alajmi, Md Imtaiyaz Hassan","doi":"10.1007/s11030-025-11104-x","DOIUrl":"https://doi.org/10.1007/s11030-025-11104-x","url":null,"abstract":"Apigenin, a dietary flavonoid with notable anti-cancer properties, has emerged as a promising candidate for the treatment of neurodegenerative disorders, particularly Alzheimer's disease (AD). While extensively studied for its ability to modulate key molecular pathways in cancers, apigenin also exerts neuroprotective effects by reducing neuroinflammation, protecting neurons from oxidative stress, and enhancing neuronal survival and synaptic plasticity. This dual functionality makes apigenin an intriguing therapeutic option for diseases like AD, where kinase dysregulation plays a central role. In this study, we focus on Microtubule Affinity-Regulating Kinase 4 (MARK4), a key enzyme implicated in tauopathies associated with AD, as well as in cancer progression. Through in silico analysis, we explore the interaction between apigenin and MARK4, revealing significant structural changes within the kinase domain upon ligand binding. These computational findings were confirmed via experimental assays using purified recombinant MARK4, where apigenin demonstrated potent inhibition with an IC50 value of 2.39 µM. Fluorescence binding assays further confirmed a strong binding affinity (Ka = 108 M-1), indicating that apigenin efficiently occupies the MARK4 active site, thereby suppressing its enzymatic activity. These results position apigenin as a potent inhibitor of MARK4, offering a dual therapeutic advantage-both as an anti-cancer agent and as a neuroprotective compound for the potential treatment of AD. This study opens new avenues for the development of apigenin-based therapeutics targeting kinase dysregulation in cancer and neurodegeneration.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998199","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}

引用次数: 0

Evaluation of methoxyflavones as dengue NS2B–NS3 protease inhibitors: an in silico and in vitro studies 甲氧基黄酮作为登革热NS2B-NS3蛋白酶抑制剂的评价：计算机和体外研究。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-01-22 DOI: 10.1007/s11030-024-10899-5

Nur Farhana Mustafa, Kian-Kai Cheng, Siti Aisyah Razali, Habibah A. Wahab, Nurul Hanim Salin, Iffah Izzati Zakaria, Muhammad Helmi Nadri

{"title":"Evaluation of methoxyflavones as dengue NS2B–NS3 protease inhibitors: an in silico and in vitro studies","authors":"Nur Farhana Mustafa, Kian-Kai Cheng, Siti Aisyah Razali, Habibah A. Wahab, Nurul Hanim Salin, Iffah Izzati Zakaria, Muhammad Helmi Nadri","doi":"10.1007/s11030-024-10899-5","DOIUrl":"10.1007/s11030-024-10899-5","url":null,"abstract":"<div>Dengue is one of the most prevalent viruses transmitted by the Aedes aegypti mosquitoes. Currently, no specific medication is available to treat dengue diseases. The NS2B–NS3 protease is vital during post-translational processing, which is a key target in this study. Due to methoxy group substitution, methoxyflavones are more bioavailable and metabolically stable than hydroxylated flavones. To date, research on the anti-dengue activity of methoxyflavones is limited. Hence, this work aims to determine the inhibitory activity of methoxyflavones against the dengue NS2B–NS3. Methoxyflavones derivatives were screened using molecular docking. The result showed a strong binding interaction of compound 1 and compound 2 with NS2B–NS3 protease. Both compounds exhibited comparable binding energy as the reference compound, quercetin, with values lower than − 8.1 kcal/mol. Molecular dynamics simulation using GROMACS revealed the stability and stiffness of the complexes over a 100 ns time scale. In addition, an in vitro assay for NS2B–NS3 protease inhibition revealed inhibitory effects of compounds 1 and 2 with IC50 values of 316.80 µM and 463.30 µM, respectively. The ADMET analyses showed favorable pharmacokinetics profiles that comply with Lipinski’s Rule of Five. Collectively, our findings suggest that compounds 1 and 2 inhibit dengue NS2B–NS3 activity. These findings hold promise of methoxyflavones as starting compounds for potential dengue treatment, highlighting the need for further investigation.</div>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":"29 2","pages":"1175 - 1187"},"PeriodicalIF":3.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998206","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}

引用次数: 0

Dual inhibition of AChE and MAO-B in Alzheimer's disease: machine learning approaches and model interpretations. AChE和MAO-B在阿尔茨海默病中的双重抑制：机器学习方法和模型解释。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-01-21 DOI: 10.1007/s11030-024-11061-x

Qinghe Hou, Yan Li

{"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":"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.","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}

引用次数: 0

Nano-sized heterogeneous photocatalyst Fe₃O₄@V/TiO₂-catalyzed synthesis and antimycobacterial evaluation of 2-substituted benzimidazoles. 纳米非均相光催化剂Fe3O4@V/ tio2催化2-取代苯并咪唑的合成及抑菌性评价。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-01-21 DOI: 10.1007/s11030-024-11085-3

Lijian Bao, Xiaodong Chen, Yanli Li, Guangyuan Zhu, Jingjun Wang, Mingyue Chen, Xingyu Bian, Qiang Gu, Yumin Zhang, Feng Lin

{"title":"Nano-sized heterogeneous photocatalyst Fe3O4@V/TiO2-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":"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.","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}

引用次数: 0

Molecular modeling aided design, synthesis and biological evaluation of quinazoline derivatives for the treatment of human cancer. 分子模拟辅助设计、合成及治疗人类癌症的喹唑啉衍生物的生物学评价。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-01-20 DOI: 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

引用次数: 0

Optimizing antibody stability and efficacy in CD47- SIRPα inhibition via computational approaches. 通过计算方法优化抗体抑制CD47- SIRPα的稳定性和有效性。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-01-20 DOI: 10.1007/s11030-024-11037-x

Kapil Laddha, M Elizabeth Sobhia

{"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":"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.","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}

引用次数: 0