In silico pharmacology最新文献

{"title":"In silico analysis of MALAT1 and H19 lncRNA interactions with the diabetes-related proteins ASK1 and YAP1.","authors":"Leonardo Elías Cabrera-Nájera, Olga Nelly Rodríguez-Peña, Cesar Mateo Flores-Ortíz, Martín Palomar-Morales","doi":"10.1007/s40203-026-00734-0","DOIUrl":"10.1007/s40203-026-00734-0","url":null,"abstract":"<p><p>Dysregulation of RNA-protein signalling networks contributes to the progression of diabetes-associated complications, yet the structural mechanisms underlying lncRNA interactions with key signalling proteins remain largely unknown. This study investigates potential interaction interfaces between MALAT1-ASK1 and H19-YAP1 using a hypothesis-generating in silico approach. A computational pipeline integrating structure prediction, molecular docking, and molecular dynamics simulations was employed. Structural assessment showed high local confidence for both proteins and lncRNAs (PAE < 1 Å) but low global lncRNA folding reliability (pTM < 0.5), consistent with intrinsic structural flexibility. ASK1 and YAP1 exhibited multiple surface cavities and disordered regions involved in signalling regulation. Docking and simulations suggested MALAT1 binding to exposed ASK1 surfaces, while H19 was predicted to associate with YAP1 regions encompassing the TEAD-binding domain and conserved regulatory phosphorylation sites, including residues corresponding to Ser109, Ser127, and Thr119. Molecular dynamics indicated transient stabilisation with persistent conformational heterogeneity. These results identify structurally plausible RNA-protein interaction interfaces that overlap with known regulatory hotspots in YAP1. Overall, this work provides a framework for experimental validation of lncRNA-mediated regulation in diabetes-related signalling pathways.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"235"},"PeriodicalIF":0.0,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148979194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational prediction of flavonoid inhibitors targeting the infectious bronchitis virus spike protein through integrated virtual screening and molecular dynamics.","authors":"Irfan Gul, Sadaf Bashir, Muttahir Aman, Amreena Hassan, Muzamil Ahmad Rather, Ubaid Sofi, Naveed Anjum Chikan, Nadeem Shabir","doi":"10.1007/s40203-026-00727-z","DOIUrl":"10.1007/s40203-026-00727-z","url":null,"abstract":"<p><p>Infectious bronchitis virus (IBV) remains a major threat to the poultry industry owing to its high transmissibility and the continuous emergence of antigenically diverse variants that compromise vaccine efficacy. The viral spike protein, which mediates host cell attachment and membrane fusion, represents an attractive target for antiviral intervention. In this study, a structure-based computational approach was employed to identify phytochemical inhibitors targeting the IBV spike protein. A curated library (PCLibVer2) comprising 2,400 phytochemicals derived from poultry-safe botanicals was subjected to hierarchical virtual screening using Glide against two receptor-binding domain-associated binding pockets. The three top-ranked lead phytochemicals were evaluated by three independent 100 ns molecular dynamics simulations, followed by trajectory-based Prime MM-GBSA binding free energy calculations and principal component analysis. All three phytochemicals exhibited favourable docking scores and stable protein-ligand interactions throughout the simulations. Molecular dynamics analyses demonstrated stable structural behaviour, persistent hydrogen-bond interactions, and reduced conformational sampling relative to the apo protein. MM-GBSA analysis predicted favourable binding free energies for all complexes, with Rutin exhibiting the strongest binding affinity at both binding pockets (- 50.07 ± 13.14 and - 55.14 ± 20.22 kcal/mol). Principal component analysis further showed that Rutin consistently produced the most compact conformational ensemble, indicating reduced protein flexibility. In silico ADMET analysis identified comparable pharmacokinetic profiles for the three lead phytochemicals. Collectively, these findings highlight the potential of flavonoid-based phytochemicals as natural inhibitors of IBV spike-mediated viral entry. This study provides a computational framework for the development of phytochemical-based interventions that may complement existing vaccination strategies and support efforts to reduce antibiotic use in poultry, pending experimental validation.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00727-z.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"222"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can docking-score differences support 5-HT2A/5-HT2B subtype-selectivity decisions? An audited paired benchmark.","authors":"Sen Ye","doi":"10.1007/s40203-026-00745-x","DOIUrl":"10.1007/s40203-026-00745-x","url":null,"abstract":"<p><p>Subtype selectivity is a paired drug-design property, and some structure-based studies infer it from score comparisons across receptors without directly validating the score difference against paired experimental selectivity. We evaluated Vina-family docking-score differences in an audited 5-HT2A/5-HT2B benchmark comprising 419 same-endpoint paired activity records, 413 unique compounds, and 411 docking-complete compounds across two structures per subtype. Experimental selectivity was ΔpX = pX(5-HT2A) - pX(5-HT2B), and docking selectivity was Δscore = mean score(5-HT2B) - mean score(5-HT2A), so positive values favored 5-HT2A. Vina Δscore gave Pearson <i>r</i> = 0.097 (95% confidence interval 0.020 to 0.173) and Spearman ρ = 0.057 (95% confidence interval - 0.039 to 0.151); both intervals lay below the predefined |r| = 0.20 practical threshold. Strong-selectivity discrimination gave an area under the receiver-operating-characteristic curve of 0.544 (95% confidence interval 0.427 to 0.664). The continuous association weakened with alternative scoring and disappeared after full Vinardo redocking. Under scaffold cross-validation, descriptor-plus-docking was indistinguishable from its ligand-only baseline. Fingerprint-plus-docking reduced error by 0.037 pX (ΔRMSE = - 0.037, 95% confidence interval - 0.051 to - 0.023); the point estimate was below the 0.05 pX practical threshold, although the interval narrowly reached it. Within this fixed, ligand-context-asymmetric, non-transducer-bound four-structure benchmark, Vina-family score-level features provide hypothesis-generating evidence rather than convincing stand-alone support for 5-HT2A/5-HT2B selectivity decisions.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00745-x.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"230"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing of DrugBank small molecules against Dengue virus capsid protein: an in silico study.","authors":"Dwaipayan Chaudhuri, Kalyan Giri","doi":"10.1007/s40203-026-00738-w","DOIUrl":"10.1007/s40203-026-00738-w","url":null,"abstract":"<p><p>Dengue virus (DENV) remains a pressing global health threat with no approved antiviral therapy to date. In this study, we explore the conserved hydrophobic pocket at the dimer interface of the dengue capsid protein as a novel target for antiviral intervention. Using a high-resolution capsid structure with modeled N-terminal disordered regions, we performed virtual screening of the entire DrugBank database employing AutoDock Vina to identify potential repurposable inhibitors. Six top-binding candidates were shortlisted based on docking scores and binding site specificity. These molecules were subjected to classical molecular dynamics (MD) simulations to evaluate complex stability, followed by thermal titration MD (TTMD) to assess interaction robustness under thermal stress. Three molecules-DB02152, DB08683, and DB13014-exhibited highly stable binding throughout both MD and TTMD analyses, with DB13014 (Hypericin) showing the highest thermal stability and favorable interaction energy. In silico ADMET profiling further validated the drug-like properties of these compounds, indicating acceptable oral bioavailability, low toxicity risk, and synthetic tractability. These findings highlight the dengue capsid hydrophobic pocket as a viable drug target and propose repurposing of small molecules as anti-dengue therapeutics.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00738-w.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"228"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational structure modeling, functional characterization, and identification of potential inhibitors for the cyclic-di-GMP mediated biofilm forming membrane protein in <i>Vibrio cholerae</i>.","authors":"Md Nahid Hasan Joy, Md Kazy Ebnul Hasan, Md Sanowar Hossan, Md Mahedi Hasan Sourov, Shahad Shahriar, Md Faruk Hasan, Amit Kumar Dutta, Md Enamul Haque","doi":"10.1007/s40203-026-00719-z","DOIUrl":"10.1007/s40203-026-00719-z","url":null,"abstract":"<p><p>Cholera, caused by <i>Vibrio cholerae</i>, continues to pose a serious global public health challenge, with its impact worsened by rising antibiotic resistance associated with bacterial biofilm formation. This study explicitly describes the role of the uncharacterised protein (UP) TYC33605.1 in cyclic-di-GMP (c-di-GMP)-mediated biofilm regulation and identifies natural computationally predicted inhibitors to disrupt this mechanism. Functional annotation revealed TYC33605.1 as a membrane-associated diguanylate cyclase (DGC) with GGDEF and sensory domains, a potential driver for c-di-GMP synthesis and biofilm persistence. Homology modelling and molecular dynamics (MD) simulations supported a plausible, stable predicted 3D structure (C-score: -1.22, Ramachandran favoured regions: 91.1%) and dynamic behaviour (average RMSD: 8.55 Å). Moreover, virtual molecular docking screening of 1,092 natural compounds identified Luteolin (CID 5280445) and Sativanone (CID 13886678) as top candidates, exhibiting strong binding affinities (- 9.1 and - 9.0 kcal/mol, respectively) and forming stable hydrogen bonds, π-cation, and hydrophobic interactions with key residues (Glu293, Arg364, Ala176). MD simulations (100 ns) were consistent with complex stability, with Luteolin and Sativanone showing lower RMSD fluctuations (7.78 and 8.13 Å) compared to the control and apoprotein. The ADME/Tox predictions indicated favourable pharmacodynamics (PD), pharmacokinetics (PK), high gastrointestinal absorption, no hepatotoxicity, and drug-likeness (Lipinski compliance). Besides, principal component, probability density function, and free energy analyses were consistent with ligand-induced conformational stability. This study proposes the molecular characterisation of the protein and the bioactive compounds Luteolin and Sativanone as promising inhibitors targeting TYC33605.1, offering a novel strategy to combat biofilm-mediated antibiotic resistance and a framework for analogous antimicrobial discovery in <i>Vibrio cholerae</i>.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00719-z.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"221"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quinoline clubbed triazole hybrids as VEGFR-2 targeted anticancer agents: synthesis, molecular modeling, and biological evaluation.","authors":"Divyanshi Thakur, Mangaldip Ghosh, Shivam Nag, Kalicharan Sharma","doi":"10.1007/s40203-026-00728-y","DOIUrl":"10.1007/s40203-026-00728-y","url":null,"abstract":"<p><strong>Abstract: </strong>Targeting tumor angiogenesis through vascular endothelial growth factor receptor-2 (VEGFR-2) remains a promising strategy for breast cancer therapy. In this present research study, a novel series of quinoline-triazole hybrids (<b>SVI01-SVI10</b>) was designed, synthesized, and evaluated as potential VEGFR-2 inhibitors. The compounds were characterized and subjected to molecular docking, MM/GBSA study and MD simulations to investigate their binding affinity and stability within the VEGFR-2 active site (PDB ID: 1Y6A). In vitro cytotoxicity against the <i>MCF</i>-<i>7</i> breast cancer cell line revealed that compound SVI08 exhibited the moderate activity (IC₅₀ = 13.5 µM), compared to the standard doxorubicin (IC₅₀ = 2.98 µM). Upon docking study, all compounds showed favourable binding interactions with Cys917 in hinge region, along with stable protein-ligand complexes during 100 ns simulations. ADMET profiling indicated acceptable drug-like properties for all compounds. Furthermore, in vivo sub-acute toxicity studies in Wistar rats confirmed that <b>SVI08</b> is well tolerated up to 50 mg/kg, with no significant histopathological abnormalities. Overall, these findings highlight quinoline-triazole hybrid <b>SVI08</b> as a preliminary lead to the further optimization as a VEGFR-2-targeted anticancer agents.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00728-y.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"227"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An integrated computational and experimental approach reveals atranorin as a promising therapeutic for non-small cell lung cancer A549 cell line.","authors":"Saparja Saha, Sayanti Karmakar, Shremayi Chatterjee, Santanu Paul","doi":"10.1007/s40203-026-00729-x","DOIUrl":"10.1007/s40203-026-00729-x","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) is the most common type of lung cancer occurring worldwide. The non-specificity and toxic side effects of conventional anti-cancer drugs have encouraged researchers to seek safer alternatives from natural sources. Atranorin, a depside group of secondary metabolites found in various lichens, possesses several pharmacological properties. Therefore, we aimed to investigate the anti-lung cancer activity of atranorin. For that, the anti-proliferative effect of atranorin was assessed and compared to that of doxorubicin against A549 lung cancer cells and BEAS-2B normal cells. Subsequently, a range of microscopic and flow cytometric evaluations were conducted to determine the apoptotic efficacy of atranorin. Furthermore, network pharmacology, combined with molecular docking, facilitated the identification of key targets. Finally, a molecular dynamics simulation was performed to verify the stability of the atranorin-target complex. Results reveal that IC₅₀ of atranorin is 15.05 ± 1.18 µM against A549 cells and has a significantly higher selectivity index than the standard drug doxorubicin. Atranorin induced robust apoptosis in the A549 cells through upregulation of phospho-p53 expression. Apoptosis was associated with the generation of intercellular ROS. A significant disruption of mitochondrial membrane potential and upregulation of Caspase-9 expression indicated that apoptosis occurred via the intrinsic pathway. Network pharmacology identified a potential target, Matrix metalloproteinase-9 (MMP-9), and in silico docking analysis revealed that atranorin has a higher binding affinity for MMP-9 than doxorubicin. Additionally, molecular dynamics simulation demonstrated the stability of the atranorin-MMP-9 complex through several parameters. Therefore, in silico and in vitro experiments confirmed the significant anticancer activity of atranorin against A549 cells.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00729-x.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"224"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative computational analysis combining network pharmacology, regulatory network modeling, and molecular dynamics reveals the mechanisms of Quanshen compound in ITP.","authors":"Maimaitiaili Yiganbaierdi, Abudoumijiti Abula, Ayitila Tuerxun, Mengyuan Wang, Xuelin Hou, Qingqing Xue, Ruiping Liang, Zihu Guo","doi":"10.1007/s40203-026-00718-0","DOIUrl":"10.1007/s40203-026-00718-0","url":null,"abstract":"<p><p>Immune thrombocytopenia (ITP) is a hemorrhagic disorder caused by immune dysfunction. Quanshen Compound (QSC) is an in-house preparation developed by the Uyghur Hospital in Hotan Prefecture. This study primarily investigates and validates the potential pharmacological basis and mechanism of action of QSC in modulating immune thrombopoiesis. Based on the multi-database screening of the QSC and the related targets of ITP, the intersection was obtained to construct a protein-protein interaction (PPI) network and screen the core targets; the intersection targets were analyzed for gene ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using R packages; a component-target-pathway network was constructed to screen the key active components and their mechanisms of action. At the same time, the TF-mRNA-miRNA regulatory network of the core targets was constructed, and chromosome localization and subcellular localization analysis were performed; further, the binding stability of key components and core targets was verified through molecular docking and molecular dynamics simulation. A total of 227 potential target sites were screened out, among which TNF, IL6, AKT1, TP53 and IL1B were the core targets. The enrichment results indicated that these intersecting target sites mainly participated in inflammatory responses, immune regulation and hemostasis-related biological processes, and were significantly enriched in the PI3K-Akt signaling pathway, Toll-like receptor signaling pathway, Th17 cell differentiation and PD-1/PD-L1 signaling pathway. The core target TF-mRNA-miRNA regulatory network contained 184 nodes and 200 edges, suggesting that the core targets were subject to multi-level regulation. Molecular docking results showed that the main active components had good binding activity with the core targets, and molecular dynamics simulation further verified the stability of the complex. QSC may improve ITP through a multi-component, multi-target, and multi-pathway synergistic mechanism involving key targets such as TNF, IL6, AKT1, TP53, and IL1B, as well as the PI3K-Akt signaling pathway. These findings provide new insights into the potential therapeutic mechanisms of QSC against ITP and warrant further experimental validation.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00718-0.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"225"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated expression profiling of BCR-ABL and computational identification of ABL1 inhibitors in pediatric acute lymphoblastic leukemia.","authors":"Shahid Ullah, Alex Tonks, Carlos Eliel Maya-Ramírez, Abdulsalam M Alruwaili, Sabahat Abdullah, Muhammad Arif Lodhi","doi":"10.1007/s40203-026-00731-3","DOIUrl":"10.1007/s40203-026-00731-3","url":null,"abstract":"<p><p>Pediatric B-cell acute lymphoblastic leukemia achieves overall survival approaching 90% with modern therapy, though high-risk subtypes, relapse, and drug resistance remain critical clinical challenges. Among its genetic abnormalities, the BCR-ABL fusion oncogene, resulting from the Philadelphia chromosome translocation t (9; 22), is associated with aggressive disease progression, poor prognosis, and high relapse rates, particularly in pediatric patients. This study aimed to investigate the expression profile of BCR-ABL in pediatric ALL and to identify potential inhibitors targeting the ABL1 tyrosine kinase using computational approaches. A cohort of 50 pediatric ALL patients was analysed and fusion oncogene expression was quantified using quantitative real-time PCR (qRT-PCR). BCR-ABL exhibited heterogeneous expression with several samples showing marked upregulation. To explore novel therapeutic options, a virtual screening workflow was employed using drug-like compounds from publicly available databases. Molecular docking identified four lead compounds (LIG1-LIG4) with higher binding affinities toward ABL1 compared to the reference inhibitor imatinib. These interactions were further characterised by favourable hydrogen bonding and hydrophobic interactions within the active site. Molecular dynamics simulations over 100 ns demonstrated the structural stability of the protein-ligand complexes, supported by acceptable RMSD and RMSF profiles. Additionally, in silico ADMET and pharmacokinetic analyses indicated that the selected compounds possess favourable drug-like properties, including high gastrointestinal absorption and acceptable safety profiles. In conclusion, this study identified BCR-ABL as the most highly expressed fusion oncogene in this cohort, consistent with its known oncogenic role in Philadelphia chromosome-positive paediatric ALL, and identifies promising ABL1 inhibitor candidates through computational screening. These findings provide a foundation for further experimental validation and the development of targeted therapies for BCR-ABL-positive ALL.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"229"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, drug-likeness, and molecular dynamics evaluations of monobrominated amathamide G analogs as potential ligands for D2-like dopamine receptors.","authors":"Angélica Navarrete-Gutiérrez, Octavio Frías-Aviña, Julio Montes-Ávila, Raúl Argüello-García, Edar O Pech-Santiago, Gerardo Aguirre-Hernández","doi":"10.1007/s40203-026-00741-1","DOIUrl":"10.1007/s40203-026-00741-1","url":null,"abstract":"<p><p>Dopamine receptors (DRs) are key modulators of physiological and behavioral responses in the central nervous system (CNS), playing a major role in psychotic disorders. Among these, the D2-like members D2R, D3R and D4R are particularly attractive therapeutic targets for the development of novel compounds derived from both synthetic and natural sources. The marine bryozoan <i>Amathia</i> produces alkaloids known as amathamides (A-H), among which the tribrominated amathamide G (AM-G) stands out as a promising scaffold. Its benzene-aliphatic linker-pentacyclic structure is reminiscent of standard dopamine antagonists such as eticlopride (ETI). In this study, a debrominated (AM-0) and monobrominated derivatives (M4B, M5B and M6B) were successfully synthesized and purified. As an initial preclinical assessment, the drug likeness profiles of these compounds were predicted and analyzed based on physicochemical properties, medicinal chemistry, and pharmacokinetic parameters. The analysis revealed that debromination of AM-G improves both lipid and aqueous solubility, enhances overall drug desirability across four major medicinal chemistry rule sets, and predicts better CNS penetration, bioavailability, half-life, and clearance, while maintaining a relatively low risk of carcinogenicity. Molecular docking and molecular dynamics (MD) simulations suggested a differential affinity amongst amathamide G derivatives towards D2-like receptors. Specifically, AM-G behaved as a high-affinity putative ligand for D3R/D4R, whereas M5B and M6B showed selectivity for D2R. These findings support continued in vitro and in vivo evaluation of these compounds, particularly in models involving expression, structure-based variations, and pathologies associated with D2R-like receptors.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00741-1.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"14 3","pages":"233"},"PeriodicalIF":0.0,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148908377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}