Journal of Biomolecular Structure & Dynamics最新文献

{"title":"Study of active ingredients and potential mechanisms of Yin-Chen-Si-Ni decoction in treating cholestatic jaundice based on UHPLC-Q-Exactive Orbitrap MS, network pharmacology, and molecular docking.","authors":"Yanru Liu, Jiayi Zheng, Gongjun Yang, Fang Feng","doi":"10.1080/07391102.2025.2521410","DOIUrl":"https://doi.org/10.1080/07391102.2025.2521410","url":null,"abstract":"<p><p>Yin-Chen-Si-Ni decoction (YCSND), as a common therapeutic practice recommendation in traditional Chinese medicine (TCM), has been applied to the management of cholestatic jaundice (CJ) syndromes. However, the effective components of YCSND and how this works have not been thoroughly documented. To elucidate the chemical map of YCSND in this work, the UHPLC-Q-Exactive Orbitrap MS analysis was carried out. Following the screening of chemical compositions for drug-likeness and oral bioavailability, multiple databases were consulted to obtain the targets of YCSND and CJ. The multiple networks were then studied to identify the core targets, effective components, and signaling pathways. Interactions between putative effective substances and important targets were assessed using molecular docking. The ideal core protein-compound complexes discovered by molecular docking were further validated using molecular dynamic simulations (MDS). According to this technique, 37 of the 172 chemical compounds that were found in the YCSND samples met the requirements for medication absorption. Network pharmacological analysis demonstrated that YCSND exhibited anti-CJ effects through quercetin, luteolin, kaempferol, glabridin, morin, and isorhamnetin acting on STAT3, EGFR, SRC, HSP90AA1, PIK3R1, ESR1, IL6, and TNF by regulating the PI3K-Akt, TNF, and MAPK signaling pathway. The anti-CJ mechanisms of YCSND might involve anti-oxidation, anti-inflammatory, apoptosis, and bile acid transport. Finally, molecular docking and MDS demonstrated that these core proteins had strong binding ability with effective components. Our integrated approach may offer methodological guidelines for investigating possible mechanisms and material foundation of TCM.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-19"},"PeriodicalIF":2.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, biological evaluation, and molecular modelling studies of novel Ethyl 3-benzoyl-6,8-dichloroindolizine-1-carboxylates against malaria vector <i>Anopheles arabiensis</i>.","authors":"Gayakvad Sunitaben Mangubhai, Pran Kishore Deb, Gourav Rakshit, Priya Tiwari, Viresh Mohanlall, Raquel M Gleiser, Mohamed A Morsy, Katharigatta N Venugopala, Sandeep Chandrashekharappa","doi":"10.1080/07391102.2025.2527142","DOIUrl":"https://doi.org/10.1080/07391102.2025.2527142","url":null,"abstract":"<p><p>A series of novel dichloroindolizine carboxylate analogues (<b>4a-n</b>) have been prepared by using 3,5-dichloropyridine, and substituted phenacyl bromide with electron-deficient acetylene <i>via</i> a [3 + 2] cycloaddition reaction. This methodology features a reaction that is free from transition metal or catalyst, providing an eco-friendly synthesis for developing dichloroindolizines. All the synthesized products (<b>4a-n</b>) were characterized by ¹H NMR,¹³C NMR, and HRMS spectroscopic techniques. All the final compounds were evaluated for larvicidal activity using Temephos as the reference standard against <i>Anopheles arabiensis</i>. Compound <b>4c</b> exhibited the highest larval mortality of 96.67% after 48 h of exposure, which is on par with the positive control, Temephos. Compounds <b>4e, 4i</b>, <b>4j,</b> and <b>4m</b> were moderately toxic, resulting in 70.00%, 74.44%, 73.33%, and 70.00% mortality, respectively, after 48 h of exposure. To validate the biological activity and elucidate a plausible mechanism of action of these compounds molecular docking studies were carried out against six known antimalarial targets. Potential compounds <b>4c</b> and <b>4e</b> showed significant binding affinities and correlation of larvicidal activity against the targets calcium-dependent protein kinase-1 (4JBV) and acetylcholinesterase from malaria vector (6ARY). Molecular dynamics studies (300 ns) further supported the stability of these compounds <b>4c</b> and <b>4e</b> inside the binding pockets of 4JBV and 6ARY, as evidenced by the RMSD, RMSF, H-bonding, and other stable interactions. Therefore, these novel indolizines can be considered as potential multi-targeting lead molecules for further optimization to combat malaria.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-18"},"PeriodicalIF":2.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comparison of anticoagulant activities of warfarin and its imino-derivatives: <i>in silico</i> molecular docking evaluation.","authors":"Imran Ali, Marwa Ghouizi, Khaled Sekkoum, Nasser Belboukhari, Khairedine Kraim, Marcello Locatelli","doi":"10.1080/07391102.2025.2527896","DOIUrl":"https://doi.org/10.1080/07391102.2025.2527896","url":null,"abstract":"<p><p>A comparison of anticoagulant activities of the enantiomers of warfarin and its imino derivatives was predicted by in silico molecular docking evaluation. The properties prediction results were calculated using the famous online server SwissADME, which showed that the studied derivatives fulfilled five Lipinski's rule of five. These results indicate that these compounds are expected to be well absorbed with good permeability and bioavailability. Furthermore, the anticoagulant activities of warfarin and its imino derivatives were investigated against vitamin K epoxide reductase using molecular docking. In this study, Molegro was the tool of choice where the new imino derivatives of warfarin have been docked within vitamin K epoxide reductase (VKOR) with PDBID: 3kp9. The docking results clearly indicated that the studied imino derivatives of warfarin have lower binding affinities, compared to warfarin with -7.4 and -8.08 kcal/mol for MNR and MAR derivatives, respectively. S-derivatives of ONS, MNS, OAS, and MAS showed to lower binding affinities with values of -5.65, -6.22, -5.26, -5.41 kcal/mole for ONS, MNS, OAS, MAS, respectively. Thus, all the studied ligands showed lower rerank scores ranged from -85.677 to -109.374, which indicated their stable bonds toward VKOR and higher biological activity. Overall, the MAR-VKOR complex was more potent derivative with a lower rerank score of -106.721 and binding affinity -8.08 kcal/mol respectively. The derivatives have shown both H bonds and steric interactions with the protein amino acids, which reflect their ability to be promiscuous the drug candidates. These findings are important to pan the experimental results for the imino derivatives.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-15"},"PeriodicalIF":2.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of azithromycin resistance in <i>Salmonella Typhi</i>: molecular insights from dynamics behavior to clinical implications.","authors":"Syeda Farishta, Rani Faryal, Muhammad Waqas, Muhammad Ali, Rizwan Uppal, Muhammad Salman, Zurva Ashraf, Asaad Khalid, Ajmal Khan","doi":"10.1080/07391102.2025.2524407","DOIUrl":"https://doi.org/10.1080/07391102.2025.2524407","url":null,"abstract":"<p><p>The widespread use of azithromycin during the COVID-19 pandemic has likely contributed to the increased resistance of <i>Salmonella Typhi</i> to this antibiotic. This study focuses on the extensive drug resistance (XDR) of <i>Salmonella Typhi</i> in Pakistan, analyzing 11,916 suspected typhoid fever cases, with 424 confirmed as <i>Salmonella Typhi</i> and Paratyphi A. Through antimicrobial susceptibility tests and PCR-based Sanger sequencing, an R717L mutation in the <i>AcrB</i> gene was identified, signalling the emergence of azithromycin resistance. This mutation was notably prevalent among XDR <i>Salmonella Typhi</i> isolates, with a high detection of <i>blaCTX-M</i> gp 1 (93%), followed by <i>blaCTX-M</i> 2 (87%) and <i>blaTEM</i> (81%). Detailed analysis revealed that the R717L mutation significantly alters the <i>AcrB</i> protein's interaction with azithromycin, evidenced by lower docking scores and reduced critical interactions, thus diminishing the antibiotic's affinity. Molecular Dynamics (MD) simulations further demonstrated that this mutation induces considerable structural changes in <i>AcrB</i>, impacting its stability and conformation. Additionally, binding free energy calculations showed decreased binding affinity of azithromycin to the mutated <i>AcrB</i> protein. These findings underscore the critical role of the R717L mutation in conferring drug resistance and highlight the urgent need for developing new antibiotic strategies to combat this growing threat. The evolution of azithromycin resistance in XDR <i>Salmonella Typhi</i> underscores the importance of cautious antibiotic use and the necessity for ongoing surveillance and research to inform effective typhoid fever treatment protocols.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-20"},"PeriodicalIF":2.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular dynamics simulation of the aggregation and folding mechanism of α-synuclein 47-56 in core peptide fragments induced by α-synuclein pentamer template.","authors":"Ruijuan Liu, Xuewei Liu","doi":"10.1080/07391102.2025.2528927","DOIUrl":"https://doi.org/10.1080/07391102.2025.2528927","url":null,"abstract":"<p><p>The misfolding of intrinsically disordered α-synuclein protein, which can form β-sheet-rich fibrillar amyloid structures, is closely associated with Parkinson's disease (PD). The peptide α-synuclein 47-56 has been identified as the toxic core of α-synuclein and plays a pivotal role in the aggregation and misfolding processes of this protein. Investigating the template induction behavior of this peptide is crucial for elucidating the molecular mechanisms underlying α-synuclein misfolding and aggregation. To explore the molecular mechanism of the peptide α-synuclein 47-56, guided by the α-synuclein pentamer template, we conducted a 400 ns molecular dynamics simulation. In this simulation, the peptide α-synuclein 47-56 was positioned on both sides of the α-synuclein pentamers. Our results demonstrate distinct elongation characteristics of the peptide α-synuclein 47-56 on the two sides of the pentamer. The β-sheet structure readily formed on the left side of the α-synuclein pentamer, facilitating template induction. In contrast, the formation of β-sheet secondary structures was hindered on the right side of the α-synuclein pentamer. Furthermore, our analysis reveals that hydrogen bonding, electrostatic interactions, and van der Waals forces between the α-synuclein pentamer and monomer are crucial for β-sheet extension. Notably, we identified the α-synuclein 49-53 region as a key peptide segment in this process.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-13"},"PeriodicalIF":2.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical exploration of different extracts from <i>Phytolacca americana</i> leaves and their potential utilization for global health problems: <i>in silico</i> and network pharmacology validation.","authors":"Nouran M Fahmy, Shaimaa Fayez, Gokhan Zengin, Selami Selvi, Abdullahi Ibrahim Uba, Adriano Mollica, Abdelhakim Bouyahya, Sathish Kumar M Ponniya, Nilofar, Sabrina Lekmine, Claudio Ferrante, Omayma A Eldahshan","doi":"10.1080/07391102.2024.2308770","DOIUrl":"10.1080/07391102.2024.2308770","url":null,"abstract":"<p><p><i>Phytolacca americana</i> L. is of great interest as a traditional additive in various folk remedies in several countries, including Turkey. We aimed to determine the chemical profile (assisted by high-Performance liquid chromatography-electrospray ionization-tandem mass apectrometry (HPLC-ESI-MS/MS) experiments of three extracts obtained by different polarity solvents viz. ethyl acetate (to extract semipolar compounds), methanol and water (to extract highly polar metabolites) from <i>P. americana</i> leaves. Their anti-diabetic effects were investigated <i>in vitro</i> by assessing their inhibition toα-amylase and α-glucosidase. Assessment of the neuroprotective potential of the three extracts was carried out against acetyl-(AChE) and butyryl-(BChE) cholinesterase enzymes. HPLC-ESI-MS/MS experiments showed a total of 17 chromatographic peaks primarily classified to six flavonoids, two saponins, and six fatty acids. Antioxidant assays revealed remarkable activity for the ethyl acetate and methanol extracts. The BChE inhibition was considerably more significant (4.08 mg galantamine equivalent (GALAE)/g) for the ethyl acetate extract, whereas the methanol extract had good inhibitory efficacy for AChE (2.05 mg GALAE/g). Through network pharmacology, the compounds' mechanism of action of targeted key gene in their associated diseases were identified. The hubb gene signal transducer and activator of transcription 3 (STAT3) and tumour necrosis factor (TNFα) where the <i>P. americana compound's</i> site of action in inflammation bowel disease. The results offer possibilities for the prospective application of <i>P. americana</i> in metabolic regulation, blood glucose control, and as a source of bioactive compounds with cholinesterase enzyme inhibitory characteristics which could be of relevance in the cosmetic or pharmaceutical industry for combating melanogenesis.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"5178-5198"},"PeriodicalIF":2.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In-vitro</i> and <i>in-silico</i> exploration of glycogen phosphorylase inhibition by <i>Aloe sinkatana</i> anthraquinones.","authors":"Mohnad Abdalla, Gihan Elhassan, Asaad Khalid, Muhammad Shafiq, Syeda Sumayya Tariq, Meshari A Alsuwat, Fatima Elfatih, Sakina Yagi, Hassan H Abdallah, Mohamad Fawzi Mahomoodally, Zaheer Ul-Haq","doi":"10.1080/07391102.2025.2524404","DOIUrl":"https://doi.org/10.1080/07391102.2025.2524404","url":null,"abstract":"<p><p>Glycogen phosphorylase (GP), a glycosyltransferase protein, was the initial allosteric enzyme identified and has since undergone thorough characterization. GP regulates the intracellular metabolization of glycogen thereby regulating blood glucose levels. Any dysfunction in this process results in altered blood glucose levels, such as Diabetes Mellitus (DM). Anthraquinones isolated from <i>Aloe sinkatana</i> have been found to possess several medicinal benefits. In this study, in-vitro techniques and computational tools were utilized to study in-depth the potential of inhibiting effects of <i>A. sinkatana</i> anthraquinones on GP. Two anthraquinones were isolated for this purpose. Their structures were elucidated and the possible effect on phosphorylase activity was assessed via an enzyme inhibition assay, where both the compounds showed substantial inhibitory activity against GP. The minimal difference between HOMO and LUMO energy levels further supported their potential binding, in line with DFT results. The binding modes and interactions were further explored in detail using in-silico studies via molecular docking and MD simulation. Results revealed strong protein-ligand interactions with Asn284 and Glu382, indicating stability. The deviations (RMSD) and fluctuations (RMSF) remained consistent, with RMSD averaging 2.2Å and RMSF around 1.5 Å. Compounds A and B are effectively bound to the receptor's active site, with -58.63 and -59.65 kcal/mol binding free energies recorded, suggesting potent GP inhibition potential. QSAR analysis revealed positive Log P values, indicating their lipophilic nature, and adhered to Lipinski's rule of 5. In conclusion these anthraquinones showed strong potential in controlling chronically elevated blood sugar levels which could help in the management of DM.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-13"},"PeriodicalIF":2.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network pharmacology and molecular dynamic simulation integrated strategy for the screening of active components and mechanisms of phytochemicals from <i>Datura innoxia</i> on Alzheimer and cognitive decline.","authors":"Mubarak A Alamri, Muhammad Tahir Ul Qamar","doi":"10.1080/07391102.2024.2308756","DOIUrl":"10.1080/07391102.2024.2308756","url":null,"abstract":"<p><p>Alzheimer's disease (AD) ranks as the most prevalent neurodegenerative disorder with dementia and it accounts for more than 70% of all cases. Despite extensive reporting on the experimental investigation of <i>Datura innoxia</i> (DI) and its phytochemical components in the treatment of AD, the urgent need for elucidation of the principle of multi-mechanism and multi-level treatment of AD remains. In this research, molecular docking and network pharmacology were used to evaluate active compounds and molecular targets of DI for the treatment of AD. The phytochemical compounds of DI were obtained from the Indian Medicinal Plants, Phytochemistry, and Therapeutics (IMPPAT) as well as the Traditional Chinese Medicine System Pharmacology (TCMSP) databases. The screening includes the 28 most abundant components of DI and the Swiss Target Prediction database was used to predict targets of these compounds. The GeneCards database was used to collect AD-related genes. Both DI and AD targets were imported into a Venn diagram, and the 28 overlapped genes were identified as potential DI anti-AD targets. The results showed that Dinoxin B, Meteloidine, Scopoline, and Tropic acid had no effect on AD-related genes. Furthermore, the GO enrichment analysis indicates that DI influences molecular functions and biological processes such as learning or memory and modulation of chemical synaptic transmission as well as the membrane raft and membrane microdomain. The KEGG pathway analysis revealed that the key pathways implicated in DI's anti-AD actions include serotonergic synapse, IL-17 signaling pathway, and AGE-RAGE signaling pathway in diabetic complications. Based on the STRING and Cytoscape network-analysis platforms, the top ten anti-AD core targets include APP, CASP3, IL6, BACE1, IL1B, ACE, PSEN1, GAPDH, GSK3B and ACHE. The molecular docking and molecular dynamic simulation of the top two molecules against the top three target proteins confirmed the strong binding affinity and stability at the docked site. Overall, our findings pave the path for further research into the development and optimization of potential anti-AD agents from DI.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"5296-5312"},"PeriodicalIF":2.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An ensemble docking-based virtual screening and molecular dynamics simulation of phytochemical compounds from Malaysian Kelulut Honey (KH) against SARS-CoV-2 target enzyme, human angiotensin-converting enzyme 2 (ACE-2).","authors":"Che Muhammad Khairul Hisyam Ismail, Azzmer Azzar Abdul Hamid, Nur Nadiah Abdul Rashid, Widya Lestari, Khairani Idah Mokhtar, Basma Ezzat Mustafa Alahmad, Mohd Ridzuan Mohd Abd Razak, Azlini Ismail","doi":"10.1080/07391102.2024.2308762","DOIUrl":"10.1080/07391102.2024.2308762","url":null,"abstract":"<p><p>The human angiotensin-converting enzyme 2 (ACE-2) receptor is a metalloenzyme that plays an important role in regulating blood pressure by modulating angiotensin II. This receptor facilitates SARS-CoV-2 entry into human cells <i>via</i> receptor-mediated endocytosis, causing the global COVID-19 pandemic and a major health crisis. Kelulut honey (KH), one of Malaysian honey recently gained attention for its distinct flavour and taste while having many nutritional and medicinal properties. Recent study demonstrates the antiviral potential of KH against SARS-CoV-2 by inhibiting ACE-2 <i>in vitro</i>, but the bioactive compound pertaining to the ACE-2 inhibition is yet unknown. An ensemble docking-based virtual screening was employed to screen the phytochemical compounds from KH with high binding affinity against the 10 best representative structures of ACE-2 that mostly formed from MD simulation. From 110 phytochemicals previously identified in KH, 27 compounds passed the ADMET analysis and proceeded to docking. Among the docked compound, SDC and FMN consistently exhibited strong binding to ACE-2's active site (-9.719 and -9.473 kcal/mol) and allosteric site (-7.305 and -7.464 kcal/mol) as compared to potent ACE-2 inhibitor, MLN 4760. Detailed trajectory analysis of MD simulation showed stable binding interaction towards active and allosteric sites of ACE-2. KH's compounds show promise in inhibiting SARS-CoV-2 binding to ACE-2 receptors, indicating potential for preventive use or as a supplement to other COVID-19 treatments. Additional research is needed to confirm KH's antiviral effects and its role in SARS-CoV-2 therapy, including prophylaxis and adjuvant treatment with vaccination.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"5393-5422"},"PeriodicalIF":2.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139570001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of 1H-pyrazolo[3,4-<i>b</i>]pyrazine derivatives as selective allosteric inhibitor of protein tyrosine phosphatase SHP2 for the treatment of KRAS^G12C-mutant non-small cell lung cancer.","authors":"Wen-Qiang Xu, Shi-Zhou Qi, Ji-Feng Zhao, Li-Peng Li, Chuan-Hua Ding, Wen-Shan Liu","doi":"10.1080/07391102.2024.2308771","DOIUrl":"10.1080/07391102.2024.2308771","url":null,"abstract":"<p><p>The high expression or mutation of SHP2 can induce cancer, so targeting SHP2 has become a new strategy for cancer treatment. In this study, we used the previously reported SHP2 allosteric inhibitor IACS-13909 as a lead drug for structural derivation and modification, and synthesized three SHP2 inhibitors. Among them, 1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyrazine derivative 4b was a highly selective SHP2 allosteric inhibitor, with an IC₅₀ value of 3.2 nM, and its inhibitory activity was 17.75 times than that of the positive control IACS-13909. The cell proliferation experiment detected that compound 4b would markedly inhibit the proliferation of various cancer cells. Interestingly, compound 4b was highly sensitive to KRAS^G12C-mutant non-small cell lung cancer NCI-H358 cells, with an IC₅₀ value of 0.58 μM and its antiproliferative activity was 4.79 times than that of IACS-13909. Furthermore, the combination therapy of compound 4b and KRAS^G12C inhibitor sotorasib would play a strong synergistic effect against NCI-H358 cells. The western blot experiment detected that compound 4b markedly downregulated the phosphorylation levels of ERK and AKT in NCI-H358 cells. Molecular docking study predicted that compound 4b bound to the allosteric site of SHP2 and formed H-bond interactions with key residues Thr108, Glu110, Arg111, and Phe113. In summary, this study aims to provide new ideas for the development of SHP2 allosteric inhibitors for the treatment of KRAS^G12C mutant non-small cell lung cancer.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"5465-5473"},"PeriodicalIF":2.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139521094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}