Molecular Diversity最新文献_第3页

An update on current type 2 diabetes mellitus (T2DM) druggable targets and drugs targeting them.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-03-13 DOI: 10.1007/s11030-025-11149-y

Prerna Uniyal, Surbhi Panwar, Akanksha Bhatt, Arockia Babu Marianesan, Roshan Kumar, Thakur Gurjeet Singh, Yogita Tyagi, Ganesh Bushi, Abhay M Gaidhane, Bhupinder Kumar

{"title":"An update on current type 2 diabetes mellitus (T2DM) druggable targets and drugs targeting them.","authors":"Prerna Uniyal, Surbhi Panwar, Akanksha Bhatt, Arockia Babu Marianesan, Roshan Kumar, Thakur Gurjeet Singh, Yogita Tyagi, Ganesh Bushi, Abhay M Gaidhane, Bhupinder Kumar","doi":"10.1007/s11030-025-11149-y","DOIUrl":"https://doi.org/10.1007/s11030-025-11149-y","url":null,"abstract":"Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia and affects millions of people globally. Even after advancement and development in medical science, it is a big task to achieve victory over type 2 diabetes mellitus (T2DM). T2DM can be a reason for fatal events like stroke, cardiac failure, nephropathy, and retinopathy. Many advanced antidiabetic drugs have been introduced in the market in the past two decades, leading researchers to hunt for new target proteins and their potential modulators that can help develop newer antidiabetic drugs. This review article comprises a broad literature of the latest developments in the management of T2DM concerning new target proteins, their inhibitors, or drugs from the clinical arena employed for the successful management of symptoms of T2DM using mono, dual, or triple combination medication therapy. The review categorizes antidiabetic drugs into three general classes that include conventional drug targets, currently explored targets, and upcoming emerging targets. The review aims to merge information on the medicines affecting these targets, their mechanisms, followed by the chemical structures, and recent advancements.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multiple pyrazolyazoindole/indazoles scaffolds-based visible-light photoswitches with versatile controlled photophysical properties.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-03-13 DOI: 10.1007/s11030-025-11161-2

Haoran Hu, Siyi Wei, Chong Zhang, Chao Gao, Chengguo Sun, Yang Du, Bingcheng Hu

{"title":"Multiple pyrazolyazoindole/indazoles scaffolds-based visible-light photoswitches with versatile controlled photophysical properties.","authors":"Haoran Hu, Siyi Wei, Chong Zhang, Chao Gao, Chengguo Sun, Yang Du, Bingcheng Hu","doi":"10.1007/s11030-025-11161-2","DOIUrl":"https://doi.org/10.1007/s11030-025-11161-2","url":null,"abstract":"Azoheteroarenes-based photoswitches with high bidirectional isomerization and long thermal half-life (t1/2) have attracted widespread attention from researchers. The diversity of molecular scaffolds has a profound impact on photoswitching performance, herein, we incorporated dynamic connection sites and scaffold optimization to construct a series of pyrazolyazoindole/indazoles (PAIs)-based photoswitches with adjustable photoswitching properties and versatile photophysical properties upon the irradiation of special wavelength, among them 4Z-H can be switched between states \"lock\" and \"unlock\" by Cu2+ ion and EDTA. Thermal stability of series 3Z and 4Z was more stable than other PAIs photoswitches for their intramolecular forces, while the steric effect weakened the thermal stability of series 5D, these results clarified the relationship between the PAIs scaffolds and their photoswitching properties. More importantly, ionic photoswitches (4D-N+) synthesized by modification of quaternary ammonium salt fragment exhibited excellent reversible photoswitching properties in aqueous solution with alkaline condition and concentrated glutathione (GSH). The assembly of fluorescence group (triphenylamine) endowed the PAIs scaffolds with optically controlled fluorescence properties. This research elucidated the relationship of scaffold-modification-function of PAIs and would inevitably provide a reliable foundation for the development of intelligent organic materials with photoswitching systems.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Computational modelling of a multiepitope vaccine targeting glycoprotein-D for herpes simplex virus 2 (HSV-2): an immunoinformatic analysis.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-03-09 DOI: 10.1007/s11030-025-11148-z

Mohd Sultan Khan, Madhvi Shakya, Chandan Kumar Verma

{"title":"Computational modelling of a multiepitope vaccine targeting glycoprotein-D for herpes simplex virus 2 (HSV-2): an immunoinformatic analysis.","authors":"Mohd Sultan Khan, Madhvi Shakya, Chandan Kumar Verma","doi":"10.1007/s11030-025-11148-z","DOIUrl":"https://doi.org/10.1007/s11030-025-11148-z","url":null,"abstract":"Herpes Simplex Virus 2 (HSV-2) infection is a global concern, affecting around 500 million individuals worldwide and being the leading cause of genital ulcers. Although several HSV vaccine candidates have been tested in humans, as of right now, neither HSV type has a licenced vaccination available. This study utilized reverse vaccinology to conduct an extensive analysis of the entire genome of HSV-2 where glycoprotein-D was chosen for T-cell epitope predictions. Through an immunoinformatic approach, we identified 2 novel CD8 + and 8 CD4 + T-cell epitopes overlapped within conformational B-cell epitopes, which hold promise as potent vaccine candidates. These epitopes were highly immunogenic and non-toxic, and also showed significant population coverage all over the world. Notably, the predicted epitopes demonstrated cross-reactivity with HSV-1, with the majority exhibiting over 80% conservation within glycoprotein-D. In addition, the designed vaccines' physicochemical properties revealed that these vaccines are non-toxic and non-allergenic, exhibited highly antigenic properties and had the potential to interact with immune receptors effectively. Furthermore, molecular docking studies with human immune receptors, specifically TLR2, demonstrated robust interactions, supported by molecular dynamics simulations indicating stable binding and dynamics. Finally, via codon optimization and in silico cloning, the vaccine candidates were successfully expressed in Escherichia coli, demonstrating feasibility for large-scale production. Computational immune response modelling following varied dosages suggested that the immunogenic constructs could elicit significant immune responses. In conclusion, this study presents promising vaccine candidates against HSV-2, utilizing a rational design approach. However, experimental validation is necessary before advancing to clinical trials.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An innovative approach to development of new pyrazolylquinolin-2-one hybrids as dual EGFR and BRAF^V600E inhibitors.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-03-08 DOI: 10.1007/s11030-025-11127-4

Mohamed M Hawwas, Ahmed S Mancy, Mohamed Ramadan, Tarek S Ibrahim, Ashraf H Bayoumi, Mohamed Alswah

{"title":"An innovative approach to development of new pyrazolylquinolin-2-one hybrids as dual EGFR and BRAFV600E inhibitors.","authors":"Mohamed M Hawwas, Ahmed S Mancy, Mohamed Ramadan, Tarek S Ibrahim, Ashraf H Bayoumi, Mohamed Alswah","doi":"10.1007/s11030-025-11127-4","DOIUrl":"10.1007/s11030-025-11127-4","url":null,"abstract":"Novel quinoline-based derivatives 2a-e and 4a-j have been designed and synthesized as potential antiproliferative agents. The designed compounds were screened for their antiproliferative activity against sixty cell lines according to NCI protocol. The promising hybrids 4d-g are screened by MTT assays on three cancer cell lines: leukemia (MOLT-4), lung cancer (HOP-92), and breast cancer (T47D), with IC50 values ranging from 4.982 ± 0.2 to 36.52 ± 1.46 µM compared to Staurosporine, with compound 4e being the most effective. Derivatives 4d-g were evaluated for their inhibitory activity on EGFR and BRAFV600E. Compound 4e exhibited the highest inhibitory activities, with IC50 values of 0.055 ± 0.002 μM for EGFR and 0.068 ± 0.003 μM for BRAFV600E, compared to the reference drugs erlotinib (IC50 0.06 ± 0.002 μM) and vemurafenib (IC50 0.035 ± 0.001 μM), respectively. Cell cycle analysis of the HOP-92 manifested that pre-G1 apoptosis signaling took place after 4e treatment. Docking simulations were employed to analyze the modes and scores of compounds 4d-g with respect to EGFR and BRAFV600E. The results revealed that compound 4e exhibited strong affinity for both EGFR and BRAFV600E compared to the reference drugs with values of - 3.226 and - 3.474 kcal/mol, respectively.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Machine learning-based activity prediction of phenoxy-imine catalysts and its structure-activity relationship study.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-03-07 DOI: 10.1007/s11030-025-11147-0

Xiaoke Zhou, Sisi He, Min Xiao, Jing He, Yuan Wang, Yuanqin Zhu, Haixiang He

{"title":"Machine learning-based activity prediction of phenoxy-imine catalysts and its structure-activity relationship study.","authors":"Xiaoke Zhou, Sisi He, Min Xiao, Jing He, Yuan Wang, Yuanqin Zhu, Haixiang He","doi":"10.1007/s11030-025-11147-0","DOIUrl":"https://doi.org/10.1007/s11030-025-11147-0","url":null,"abstract":"This study systematically investigates the structure-activity relationships of 30 Ti-phenoxy-imine (FI-Ti) catalysts using machine learning (ML) approaches. Among the tested algorithms, XGBoost demonstrated superior predictive performance, achieving R2 values of 0.998 (training set) and 0.859 (test set), with a cross-validated Q2 of 0.617. Feature importance analysis identified three composite descriptors-ODI_HOMO_1_Neg_Average GGI2, ALIEmax GATS8d, and Mol_Size_L-as critical contributors, collectively accounting for > 63% of the model's predictive power. Polynomial feature expansion effectively captured nonlinear interactions between descriptors, while SHAP and ICE analyses enhanced interpretability, revealing threshold effects and descriptor-specific trends. However, the model's generalizability may be constrained by the limited dataset size (30 samples) and reliance on density functional theory (DFT)-derived descriptors, necessitating experimental validation. Additionally, the study focused solely on ethylene polymerization at 40 °C; broader applicability to diverse catalytic systems or reaction conditions requires further validation. These findings provide a data-driven framework for catalyst design, though future work should integrate experimental validation and expand datasets to refine predictive robustness.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of novel melatonin-isatin hybrids as multifunctional agents for Alzheimer's disease.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-03-04 DOI: 10.1007/s11030-025-11129-2

Ying-Ying Zhong, Jun-Ze Deng, Qin Wang, Li Chen, Zi-Hang Yang, Ya-Mei Zhang, Lu-Yi Zhou, Yi-Ran Li, Jia-Qiang Wu, Xiao-Qin Wang

{"title":"Development of novel melatonin-isatin hybrids as multifunctional agents for Alzheimer's disease.","authors":"Ying-Ying Zhong, Jun-Ze Deng, Qin Wang, Li Chen, Zi-Hang Yang, Ya-Mei Zhang, Lu-Yi Zhou, Yi-Ran Li, Jia-Qiang Wu, Xiao-Qin Wang","doi":"10.1007/s11030-025-11129-2","DOIUrl":"https://doi.org/10.1007/s11030-025-11129-2","url":null,"abstract":"The development of multifunctional agents has been a heated area of research for AD treatment in recent years. In this work, a series of melatonin-isatin hybrids were designed, synthesized, and evaluated as multifunctional agents for treating AD. In vitro studies indicated that most of the synthesized compounds displayed moderate to good MAO-B inhibition activities and good antioxidant activities. In particular, compounds IM-5 and IM-10 exhibited the best inhibitory activities with IC50 value of 12.4 μM and 15.6 μM against MAO-B, and potent antioxidant activities with their ORAC-FL values of 4.6 and 5.2 at 5 μM, respectively. ThT assay revealed compounds IM-5 and IM-10 exhibited the optimal Aβ1-42 self-induced aggregation inhibitory activities with the inhibition ratio of 72.8% and 69.7% at 20 μM. In addition, compounds IM-5 and IM-10 exhibited low cytotoxicities and significant neuroprotective effects on Aβ1-42-induced and H2O2-induced SH-SY5Y cell injury. More importantly, compounds IM-5 and IM-10 could significantly ameliorate the memory impairment and cognition injury in scopolamine-induced mice. The SwissADME program was used to predict drug-like properties of compounds IM-5 and IM-10 which exhibited they had good pharmacokinetics and drug-likeness properties. Molecular docking study further manifested that compounds IM-5 and IM-10 showed high hMAO-B inhibitory potency. In summary, all above results revealed compounds IM-5 and IM-10 might be promising multifunctional agents for AD treatment.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis, DFT study, in silico ADMET evaluation, molecular docking, and QSAR analysis of new anti-tuberculosis drugs derived from 2-hydroxybenzohydrazide derivatives.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-03-01 DOI: 10.1007/s11030-025-11130-9

Alaa E Hassanien, Ghada Elsherbiny, Gamal M Abdelfattah, Marwa M Abdel-Aziz, Eman A El-Hagrassey

{"title":"Synthesis, DFT study, in silico ADMET evaluation, molecular docking, and QSAR analysis of new anti-tuberculosis drugs derived from 2-hydroxybenzohydrazide derivatives.","authors":"Alaa E Hassanien, Ghada Elsherbiny, Gamal M Abdelfattah, Marwa M Abdel-Aziz, Eman A El-Hagrassey","doi":"10.1007/s11030-025-11130-9","DOIUrl":"https://doi.org/10.1007/s11030-025-11130-9","url":null,"abstract":"This study investigates the potential of novel thiazole and hydroxybenzohydrazide derivatives as antitubercular agents. Using molecular docking and density functional theory (DFT) calculations, the binding affinities of these derivatives to the enoyl-acyl carrier protein reductase (InhA) enzyme of M. tb were assessed. InhA is crucial for the mycobacterial fatty acid synthase II (FAS-II) pathway, making it a prime target for drug development. QSAR analysis was employed to relate molecular descriptors to biological activity, and ADMET descriptors evaluated the pharmacokinetics and toxicity of the compounds. Experimental synthesis of the compounds and their characterization via IR and NMR spectroscopy confirmed their structures. DFT calculations revealed multiple conformers for each compound, with specific isomers showing enhanced stability and favorable binding interactions with InhA. These findings suggest that the synthesized derivatives have potential as new antitubercular agents, offering a basis for future drug development strategies against multidrug-resistant TB.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530855","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

Computational framework for minimizing off-target toxicity in capecitabine treatment using natural compounds. 利用天然化合物最大限度降低卡培他滨治疗脱靶毒性的计算框架。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-02-26 DOI: 10.1007/s11030-025-11139-0

Tanya Jamal, Anamta Ali, Shweta Singh Chauhan, Rinni Singh, Ramakrishnan Parthasarathi

{"title":"Computational framework for minimizing off-target toxicity in capecitabine treatment using natural compounds.","authors":"Tanya Jamal, Anamta Ali, Shweta Singh Chauhan, Rinni Singh, Ramakrishnan Parthasarathi","doi":"10.1007/s11030-025-11139-0","DOIUrl":"https://doi.org/10.1007/s11030-025-11139-0","url":null,"abstract":"Antineoplastic drugs are becoming prevalent due to increasing cancer casualties around the globe. However, the adverse effects of these drugs are evident due to limited insight into the underlying mechanisms that result in non-specific binding and consequent off-target toxicity. The study investigates the side effects of an antineoplastic drug, Capecitabine, a prodrug converted into fluorouracil by Thymidine Phosphorylase (TP) and degrades the RNA of cancerous cells. However, its non-specific binding with Dihydropyrimidine dehydrogenase (DPD) leads to severe toxicities including leukoencephalopathy, neutropenia, neuropathy, and others. Hence, identifying natural analogs of Capecitabine with comparable attributes is crucial for minimizing its adverse effects. A thorough review of the literature revealed Capecitabine-induced toxicity. 723,878 natural compounds were screened, and drug-like mimics were identified. Their binding with TP and DPD was determined by employing molecular docking, which was validated by MD simulations evaluating conformational stability and variability. Four natural compounds showed better docking scores than the standard drug. The stability of the best hit was further validated with MD simulations. This study, hence, ushers in new perspectives on safer drug alternatives using potent natural analogs and could serve as a lead identification approach for the discovery of safer therapeutics.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497766","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

Integrating network pharmacology, molecular docking, and bioinformatics to explore the mechanism of sparganii rhizoma in the treatment of laryngeal cancer. 整合网络药理学、分子对接和生物信息学，探索刺五加根茎药治疗喉癌的机制

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-02-26 DOI: 10.1007/s11030-025-11142-5

Meiling Zheng, Rui Zhang, Xinxing Yang, Feiyan Wang, Xiaodi Guo, Long Li, Jin Wang, Yajun Shi, Shan Miao, Wei Quan, Shanbo Ma, Xiaopeng Shi

{"title":"Integrating network pharmacology, molecular docking, and bioinformatics to explore the mechanism of sparganii rhizoma in the treatment of laryngeal cancer.","authors":"Meiling Zheng, Rui Zhang, Xinxing Yang, Feiyan Wang, Xiaodi Guo, Long Li, Jin Wang, Yajun Shi, Shan Miao, Wei Quan, Shanbo Ma, Xiaopeng Shi","doi":"10.1007/s11030-025-11142-5","DOIUrl":"https://doi.org/10.1007/s11030-025-11142-5","url":null,"abstract":"Sparganii Rhizoma (SR) has demonstrated promising anticancer effects across various malignancies; however, its mechanisms in laryngeal cancer (LC) remain poorly understood. This study employs network pharmacology and molecular docking to investigate the molecular mechanisms underlying SR's therapeutic effects on LC, providing novel insights for its potential use in treatment. Active compounds and targets of SR were identified through the TCMSP and Pharmmapper databases, while LC-related targets were sourced from GEO, GeneCards, OMIM, and PharmGkb databases. A Venn diagram generated from these datasets highlighted 58 overlapping targets. The STRING database and Cytoscape 3.9.1 software facilitated the construction of a protein-protein interaction network for these targets, and R language analysis revealed 15 core targets. GO and KEGG enrichment analyses, conducted with the ''clusterProfiler'' package, identified relevant biological processes, cellular components, and molecular functions associated with LC treatment. KEGG analysis suggested SR primarily regulates pathways such as TNF, IL-17, and P53. Molecular docking confirmed SR's ability to bind effectively to the 15 core targets. Molecular dynamics simulations further validated stable protein-ligand interactions for MAPK1, GSK3B, and MAPK14. Core target validation across transcriptional, translational, and immune infiltration levels was performed using GEPIA, HPA, cBioPortal, and TIMER databases. In conclusion, network pharmacology, molecular docking, and dynamics simulations provided insights into SR's mechanism in LC treatment, forming a theoretical basis for further investigation of its therapeutic potential.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497770","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

Structural insights of AKT and its activation mechanism for drug development.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2025-02-26 DOI: 10.1007/s11030-025-11132-7

B Harish Kumar, Shama Prasada Kabekkodu, K Sreedhara Ranganath Pai

{"title":"Structural insights of AKT and its activation mechanism for drug development.","authors":"B Harish Kumar, Shama Prasada Kabekkodu, K Sreedhara Ranganath Pai","doi":"10.1007/s11030-025-11132-7","DOIUrl":"https://doi.org/10.1007/s11030-025-11132-7","url":null,"abstract":"AKT1, a serine/threonine kinase, is pivotal in signaling and regulating cell survival, proliferation, and metabolism. This review focuses on the structural insights and the essential features required for its active conformation. AKT belongs to the AGC kinase group and has three isoforms: AKT1, AKT2, and AKT3. AKT has three functional regions: PH domain, kinase domain, and hydrophobic motif. AKT1 activation involves intricate conformational changes, including transitions in the αC-in, DFG-in, G-loop, activation loop, and PH domain out, S-spine and R-spine formation, as well as phosphorylation at Thr 308 and Ser 473, which enable AKT1 to adopt active conformation. The analysis highlights the limitations of the AlphaFold-predicted AKT1 structure, which lacks key elements of the active state, including ATP, magnesium ion coordination, phosphatidylinositol-(1,3,4,5)-tetraphosphate, substrate peptide, and phosphorylation at Thr 308 and Ser 473. This study underscores the necessity of these features for stabilizing the kinase domain and facilitating efficient substrate phosphorylation. By consolidating structural insights and activation mechanisms, this review aims to inform the development of computational models and targeted therapeutics for AKT1 activators in diseases such as hepatic ischemia-reperfusion injury, cerebral ischemia, acute hepatic failure, subarachnoid hemorrhage, and alzheimer's disease.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497773","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