Journal of Computer-Aided Molecular Design最新文献

{"title":"Protein domain movement involved in binding of belinostat and HPOB as inhibitors of histone deacetylase 6 (HDAC6): a hybrid automated-interactive docking study","authors":"Georgios Iakovou,&nbsp;L. Palmer,&nbsp;A. Ganesan,&nbsp;Akio Kitao,&nbsp;Stephen D. Laycock,&nbsp;Steven Hayward","doi":"10.1007/s10822-025-00636-x","DOIUrl":"10.1007/s10822-025-00636-x","url":null,"abstract":"<div><p>DockIT is a tool for interactive molecular docking that can model both the local and global conformational response of the receptor to the docking of a ligand based on information from a molecular dynamics simulation. Using DockIT we have investigated the binding process of two histone deacetylase (HDAC) inhibitors to HDAC6: the nonselective approved drug belinostat and the preclinical HPOB. To model HDAC6’s conformational response to the binding of the inhibitors we performed a 200-nanosecond explicit-solvent molecular dynamics simulation on HDAC6. Unexpectedly the simulation revealed a domain movement that affects the size and shape of the binding pocket. Using automated docking and a rigid model for the inhibitors, the domain movement continuously adapts the pocket to the presence of the inhibitor. For both inhibitors, an intermediate binding site was found where it was partially inserted, with a hydrogen bond formed between the inhibitor’s hydroxamic acid and the Tyr745 side chain. Pushing the inhibitor deeper into the pocket over an energy barrier and re-engaging automated docking, a final binding pose resulted with a root-mean square deviation with its respective crystallographic pose of 1.0 Å for belinostat and 1.4 Å for HPOB. We believe our results mimic substrate recognition by the enzyme, with an initial partial binding of the acetyllysine residue with Tyr745. During binding a relay of hydrogen bonds occurs coordinating the orientation of the cap and the hydroxamic acid inside the pocket. The interaction between the cap and the surface of HDAC6 explains the reason for the hydroxamic acid warhead in HPOB binding in a flipped orientation compared to belinostat.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"“Heptadecanol” a phytochemical multi-target inhibitor of SMYD3 & GFPT2 proteins in non-small cell lung cancer: an in-silico & in-vitro investigation","authors":"Lokesh Ravi,&nbsp;Pratishtha Jain,&nbsp;Ajith Kumar K,&nbsp;Jeevan Kumar M,&nbsp;Mukti Panda,&nbsp;Harshitha S,&nbsp;Mohammed Abdul Kareem,&nbsp;K. Sivani Yelchuri Sai,&nbsp;Ayman Fathima,&nbsp;V. Jensha,&nbsp;Adarsh Anurag Rai,&nbsp;Hida Amal Faizal,&nbsp;Shrivats S R,&nbsp;Ankitha Ajith,&nbsp;Derick Yesudas,&nbsp;Vaarruni S,&nbsp;Varshini S,&nbsp;Raksha Shetty,&nbsp;Aditi Jha,&nbsp;Gundlapalli Saradha Janaki,&nbsp;Varsha Hannah George,&nbsp;Stalin Nithaniyal,&nbsp;Mookkandi Palsamy Kesavan,&nbsp;Sajith Ahamed A,&nbsp;Sankara Narayanan A","doi":"10.1007/s10822-025-00627-y","DOIUrl":"10.1007/s10822-025-00627-y","url":null,"abstract":"<div><p>Understanding the mechanism of action of anticancer agent plays a key role in effective clinical application of natural products. This study aims to identify an anti-cancer phytochemical with multi-target inhibition potential against non-small cell lung cancer. This study employs virtual screening of 8352 phytochemicals by molecular docking (AutoDock Vina &amp; SeeSAR) to identify potential inhibitor of KRas, SMYD3, ALDH1 and GFPT2 proteins. Molecular Dynamics Simulation (Desmond) simulation for extensive 500 ns duration was performed to validate the inhibition potential. Followed by cell biology studies i.e., MTT assay, Flowcytometry and qRT-PCR analysis to confirm the mechanism of action. Molecular Docking and Molecular Dynamics Simulation studies predicted Heptadecanol as potential inhibitor of three drug targets, i.e., KRas, SMYD3 and GFPT2. In-vitro cytotoxicity assay confirmed the anti-cancer cytotoxicity of Heptadecanol with a significant IC₅₀ value of 3.12 µg/ml selectively target cancer cells (A549), without substantial toxicity to non-cancerous cells (L929) with IC₅₀ of &gt; 100 µg/ml. Flowcytometry analysis with Annexin-V and Propedium Iodide staining further confirmed the apoptotic potential of Heptadecanol against A549 cells. qRT-PCR analysis demonstrated a robust increase in GFPT2 (25.6 × fold) and SMYD3 (16.98 × fold) gene expression, that conclusively confirmed the multi-target inhibition potential of Heptadecanol. Results of the study concludes that Heptadecanol is a significant inhibitor of GFPT2 and SMYD3 protein, there by exhibiting selective anti-cancer activity against the investigated non-small cell lung cancer cells. Further in-vivo studies are in demand to quantify the anti-cancer efficacy in a living system.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635858","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":"Therapeutic potency of a developed optimized polyherbal formulation in ameliorating obesity induced inflammation and oxidative stress in Swiss albino mice by targeting PPARγ, insulin receptor and AMPK signalling pathway","authors":"Pritimoni Das,&nbsp;Manas Das","doi":"10.1007/s10822-025-00625-0","DOIUrl":"10.1007/s10822-025-00625-0","url":null,"abstract":"<div><p>High fat diet (HFD) induced obesity plays a key role in onset of inflammation, a chronic response of the body to elevated expression of proinflammatory cytokines. Our work emphasized on assessing the therapeutic potency of the polyherbal formulations (PHF), composed of <i>Phyllanthus urinaria</i> and <i>Adhatoda vascia nees</i> by studying the expression pattern of <i>iNOS</i>, pro, anti-inflammatory cytokines, chemokine along with identification of potent anti-inflammatory compounds in HFD induced inflammation in four weeks old (23–25 g bw, n = 6 in triplcates) Swiss albino mice. The findings demonstrated high percentage of free radical scavenging property of PHF, downregulation of expression level of proinflammatory cytokines and chemokines, profound elevation of anti-inflammatory cytokines, anti-oxidant enzymes in both PHF treated groups signifying protection against oxidative stress. In silico study revealed binding energy of Okanin, Vomicine, Granisetron and Pisdic acid − 9.31 kcal/mol, − 8.34 kcal/mol, − 8.10 kcal/mol, − 7.93 kcal/mol respectively with strong protein ligand interaction with inflammatory, lipid marker PPARγ and insulin resistance marker protein receptor INSR. Among other four ligands, Peganine, Coralyne, Soraphen O and 2-hydroxyhexadecanoic acid; Soraphen O and Coralyne showed best binding affinity with INSR (− 6.8 kcal/mol) and PPARγ (− 6.9 kcal/mol) respectively. The evaluation based on network pharmacology, the active ingredients of the PHF for AMPK signalling pathway and protein analysis identified 121 targets. A network of interaction between the eight ligands and known therapeutic targets of INSR and AMPK depicted pharmacological mechanisms of the PHF in inhibition of insulin resistance by activating INSR and AMPK-pathway thus establishing itself as potent alternative drug in treating ailments associated with obesity induced inflammation.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635859","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":"CoBdock-2: enhancing blind docking performance through hybrid feature selection combining ensemble and multimodel feature selection approaches","authors":"Sadettin Y. Ugurlu","doi":"10.1007/s10822-025-00629-w","DOIUrl":"10.1007/s10822-025-00629-w","url":null,"abstract":"<div><p>Identifying orthosteric binding sites and predicting small molecule affinities remains a key challenge in virtual screening. While blind docking explores the entire protein surface, its precision is hindered by the vast search space. Cavity detection-guided docking improves accuracy by narrowing focus to predicted pockets, but its effectiveness depends heavily on the quality of cavity detection tools. To overcome these limitations, we developed <b>Co</b>nsensus <b>B</b>lind <b>Dock</b> (CoBDock), a machine learning-based blind docking method that integrates molecular docking and cavity detection results to enhance binding site and pose prediction. Building on this, <b>CoBDock-2</b> replaces traditional docking tools by extracting 1D numerical representations from protein, ligand, and interaction structural features, and applying advanced ensemble feature selection techniques. By evaluating 21 feature selection methods across 9,598 features, CoBDock-2 identifies key molecular characteristics of orthosteric binding sites. CoBDock-2 demonstrates consistent improvements over the original CoBDock across benchmark datasets (PDBBind v2020-general, MTi, ADS, DUD-E, CASF-2016), achieving 77% binding site identification accuracy (within 8 Å), 55% ligand pose prediction accuracy (RMSD <span>(le)</span> 2 Å), a 19% reduction in the mean distance to ground truth ligands within the binding site, and an 18.5% decrease in the mean pose RMSD. Statistical analysis across the combined benchmark set confirms the significance of these improvements (<span>(text {p} &lt; 0.05)</span>). Notably, the Weighted Hybrid Feature Selection variant in CoBDock-2 further increases binding site accuracy to 79.8%, demonstrating the benefit of combining multimodel and ensemble feature selection strategies. Variability in predictions also decreased significantly, highlighting enhanced reliability and generalizability. Also, a low-bias hypothetical comparison with a state-of-the-art DiffDock + NMDN method was conducted to position CoBDock-2 relative to modern deep learning-based docking strategies.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615678","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":"New alkyl triphenylphosphonium dipterocarpol derivatives with cytotoxicity against the MCF-7 breast cancer cell line","authors":"Tu H. Tran,&nbsp;Tho H. Le,&nbsp;Thu-Ha T. Nguyen,&nbsp;Long B. Vong,&nbsp;Mai T. T. Nguyen,&nbsp;Nhan T. Nguyen,&nbsp;Phu H. Dang","doi":"10.1007/s10822-025-00631-2","DOIUrl":"10.1007/s10822-025-00631-2","url":null,"abstract":"<div><p>Dipterocarpol exhibited cytotoxic properties; however, its hydrophobic nature resulted in decreased bioavailability. This study successfully synthesized six new alkyl triphenylphosphonium dipterocarpol derivatives (<b>1</b>–<b>6</b>) with good yield. These derivatives demonstrated enhanced cytotoxic potency against MCF-7, an estrogen receptor <i>α</i>-positive (ER<i>α</i>+) breast cancer cell line (IC₅₀, 1.84–24.72 <i>µ</i>M), compared to dipterocarpol (IC₅₀ &gt; 100 <i>µ</i>M). To unveil their mechanism of action, molecular docking analyses were performed with ER<i>α</i>, a therapeutic target for the treatment of ER + breast cancers. Furthermore, molecular dynamics simulations of the two most potent compounds (<b>2</b> and <b>4</b>) complexed with both ER<i>α</i> forms indicated that these compounds could function as favourable antagonists. Based on the in silico studies, compound <b>4</b> was showed to be more potent than compound <b>2</b>, which was consistent with the cytotoxicity data (IC₅₀, 1.84 <i>µ</i>M for <b>4</b> and 2.13 <i>µ</i>M for <b>2</b>). In silico pharmacokinetic predictions, informed by assessments of Lipinski compliance, logD, TPSA, human intestinal absorption potential, volume of distribution, and Tox21, suggested that compounds <b>2</b> and <b>4</b> may serve as potential drug candidates.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615679","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":"Anti-inflammatory potential of isoquinoline alkaloids from Fumaria officinalis: in vitro, in vivo, and in silico evaluation","authors":"Sonia Yahiaoui,&nbsp;Sabiha Khamtache-Abderrahim,&nbsp;Djamel Edine Kati,&nbsp;Nadir Bettache,&nbsp;Mostapha Bachir-bey","doi":"10.1007/s10822-025-00628-x","DOIUrl":"10.1007/s10822-025-00628-x","url":null,"abstract":"<div><p>The objective of this study is to identify the alkaloids of <i>Fumaria officinalis</i> and to evaluate their anti-inflammatory activity through three approaches in vitro, in vivo and in silico. In vitro and in vivo anti-inflammatory activities were evaluated using the BSA denaturation method and induction of paw edema by carrageenan. In silico molecular docking and ADME/T studies were carried out to evaluate the potential of the identified alkaloid compounds against cyclooxygenase-II (COX-2) enzyme. The LC-MS/MS analysis results revealed the presence of 17 isoquinoline alkaloids, among which jatrorrhizine and protopine were the most abundant, with percentages of 29.29 and 8%, respectively. The extract of <i>F. officinalis</i> demonstrated maximum BSA protection at a concentration of 500 µg/mL (76.16% efficiency). Furthermore, the extract showed a dose-dependent anti-inflammatory effect on carrageenan-induced paw edema, with the best effect observed at the 6th hour in mice treated with 200 mg/kg of alkaloid extract (77% efficiency). Molecular docking revealed that protopine, bicuculline, stylopine, and coptisine exhibited high affinity to the receptor (with high interaction energy by around 10), with strong hydrogen and hydrophobic bonds. Stylopine fulfilled all ADME/T conditions and did not present any toxicity. In addition, quantum chemical analysis of stylopine confirmed its electronic stability and reactivity, supporting its potential as a COX-2 inhibitor. These findings demonstrate that the stylopine could be considered a powerful anti-inflammatory compound.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615677","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":"Disrupting tuberculosis pathogenesis by targeting DprE1 in cell wall biosynthesis: a structural dynamics perspective","authors":"Abdulwahab Alamri,&nbsp;Ahmed Alafnan,&nbsp;Weiam A. Hussein,&nbsp;Khaled Almansour,&nbsp;Alrafidi Rafidi Dhham,&nbsp;Amr S. Abouzied","doi":"10.1007/s10822-025-00626-z","DOIUrl":"10.1007/s10822-025-00626-z","url":null,"abstract":"<div>\u0000 \u0000 <p><i>Mycobacterium tuberculosis</i> (Mtb), the causative agent of TB, remains a major global health challenge due to the emergence of MDR and XDR strains. Targeting DprE1, an enzyme essential in the biosynthesis of the mycobacterial cell wall, offers a promising therapeutic strategy. The current work utilized a computational pipeline for identifying potential inhibitors of DprE1 from the Diverse-lib database by virtual screening, molecular docking, molecular dynamics, free binding energy calculation, and free energy landscape analysis based on RMSD and Rg values. Three candidates were identified as promising inhibitors out of all the screened diverse-lib compounds. Their binding poses and interaction patterns were analyzed and compared with those of a known reference inhibitor. In molecular docking, three compounds showed high binding affinities, while MD simulations further showed stable protein-ligand complexes for more than 300 nsec in quadruplicate. Free binding energy calculation through MM/GBSA revealed energetically favorable interactions. From this RMSD-Rg-based free energy landscape, the stability in conformation was indicated in the complexes. Minima structures also strongly agreed with initial poses, evidenced by superimposition analysis. Comparison with the reference molecule revealed that the identified compounds exhibit comparable or higher binding energies and structural stability, suggesting their potential to inhibit DprE1. These findings warrant further experimental validation to confirm their efficacy against Mtb.</p>\u0000 </div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590179","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":"Machine learning-based QSAR and structure-based virtual screening guided discovery of novel mIDH1 inhibitors from natural products","authors":"Hailong Bai,&nbsp;Yalong Cheng,&nbsp;Shunjiang Jia,&nbsp;Xiaorui Wang,&nbsp;Ruyi Jin,&nbsp;Hui Guo,&nbsp;Yuping Tang,&nbsp;Yuwei Wang","doi":"10.1007/s10822-025-00624-1","DOIUrl":"10.1007/s10822-025-00624-1","url":null,"abstract":"<div><p>Mutations in isocitrate dehydrogenase 1 (IDH1) have been widely observed in various tumors, such as gliomas and acute myeloid leukemia, and therefore has become one of the current research focal points. Therefore, it is crucial to find inhibitors that could target mIDH1, which may provide more effective treatment options for patients with related tumors. In present study, combines machine learning-based QSAR models and structure-based virtual screening to screen a series of potential IDH1 inhibitors from the Coconut databases. The QSAR model predictions indicate that the hit compounds have high binding affinity to the target protein, and its pIC₅₀ value was found to be considerably larger than that of AGI-5198. The RMSD and Rg analysis demonstrated that all of the ligand–protein complexes exhibited a stable state throughout the simulation period. Furthermore, the binding free energy decomposition and per-residue contribution of the IDH1^R132H-inhibitor complex revealed key fragments of the inhibitor interacting with residues ALA-111, PRO-118, ARG-119, LE-128, ILE-130, ITRP-267, VAL-281, and TYR-285 in the binding site of IDH1^R132H. This investigation indicates that CNP0047068, CNP0029964, and CNP0025598 have the potential to be targeted inhibitors of IDH1^R132H mutants through further optimization, providing new insights for discovering novel lead scaffolds in this domain.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590180","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 computational study of cardiac glycosides from Vernonia amygdalina as PI3K inhibitors for targeting HER2 positive breast cancer","authors":"Ahmad Syauqy Tafrihani,&nbsp;Naufa Hanif,&nbsp;I Made Bayu Kresna Yoga,&nbsp;Irmasari Irmasari,&nbsp;Taufik Muhammad Fakih,&nbsp;Dhania Novitasari,&nbsp;Poppy Anjelisa Zaitun Hasibuan,&nbsp;Denny Satria,&nbsp;Fathul Huda,&nbsp;Muchtaridi Muchtaridi,&nbsp;Adam Hermawan","doi":"10.1007/s10822-025-00621-4","DOIUrl":"10.1007/s10822-025-00621-4","url":null,"abstract":"<div><p>The PI3K/Akt pathway plays a crucial role in regulating a broad network of proteins involved in the proliferation of HER2-positive breast cancer. The ethyl acetate fraction of <i>Vernonia amygdalina</i>, which contains cardiac glycosides, has been shown to reduce the expression of PI3K and mTOR. However, the specific cardiac glycoside compounds with significant potential as PI3K inhibitors have yet to be clearly identified. This study employs machine learning to perform virtual screening of cardiac glycosides from <i>V. amygdalina</i> against the p110 subunit of PI3K. Initially, Lipinski’s Rule of Five was used to filter the PIK3CA inhibitor database via KNIME software. Subsequently, QSAR modeling was conducted using KNIME’s machine learning platform, employing six different algorithms. Cardiac glycosides from <i>V. amygdalina</i> were then evaluated using the best-performing QSAR model. The top three compounds identified underwent molecular docking and molecular dynamics simulations. The random forest algorithm was selected as the primary predictive model, which identified Vernoamyosides A (VG-1), Vernoniamyosides D (VG-8), and Vernoniosides A4 (VG-10) as the compounds with the highest confidence levels. Molecular docking results indicated that these three compounds exhibited stronger and more stable interactions with the PIK3CA receptor compared to alpelisib, a known PIK3CA inhibitor. Furthermore, molecular dynamics simulations revealed that VG-10 had the lowest binding free energy, as determined by MM-GBSA analysis. The findings of this study provide a foundational basis for preclinical and clinical investigations aimed at developing PI3K inhibitors derived from cardiac glycosides of <i>V. amygdalina</i> for the treatment of HER2+ breast cancer.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574639","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":"3CLpro of SARS-CoV-2 as a new target for bufadienolides: in silico and in vitro study","authors":"Muzaffar Kayumov,&nbsp;Jamoliddin Razzokov,&nbsp;Mukhriddin Makhkamov,&nbsp;Murodjon Radjabov,&nbsp;Nurkhodja Mukhamedov,&nbsp;Makhmudjon Khakimov,&nbsp;Akmal M. Asrorov,&nbsp;Okhunjon Khasanov,&nbsp;Ansor Yashinov,&nbsp;Mugrajitdin Tashmukhamedov,&nbsp;Ahmidin Wali,&nbsp;Abulimiti Yili,&nbsp;Sharafitdin Mirzaakhmedov","doi":"10.1007/s10822-025-00623-2","DOIUrl":"10.1007/s10822-025-00623-2","url":null,"abstract":"<div><p>The rapid spread of SARS-CoV-2 and its widespread public health implications have highlighted the urgent need for effective antiviral therapies. A promising strategy is to investigate natural compounds that may inhibit the key viral targets. In this work, we demonstrated the anti-SARS-CoV-2 activity of six bufadienolides, including bufalin (A), arenobufagin (B), gamabufotalin (C), telocinobufagin (D), marinobufagin (E), and bufarenogin (F) from the venom of the Central Asian green toad, <i>Bufo viridis</i>. Molecular docking assays revealed that all A-F bufadienolides bind to key residues (Thr26, His41, Met49, Met161, and Gln189) in the catalytic pocket of 3-chymotrypsin-like cysteine protease (3CL^pro), an essential enzyme for viral replication and polyprotein processing. The stability of the protein-ligand complexes was then tested using molecular dynamics (MD) simulations, while the binding free energies were estimated using the umbrella sampling (US) technique. Compounds A (-49.8 ± 1.0 kJ/mol), C (-45.9 ± 1.8 kJ/mol), E (-45.6 ± 1.1 kJ/mol), and F (-45.8 ± 1.9 kJ/mol) had significantly higher binding affinities than compounds B (-14.6 ± 1.1 kJ/mol) and D (-10.3 ± 1.9 kJ/mol). In vitro enzymatic assays also confirmed these results, demonstrating that A and C exhibited potent inhibitory activity against 3CL^pro with IC₅₀ values of 1.37 µM and 2 µM, respectively, compared to the other bufadienolides; however, they were less active than the positive control GC376 (IC₅₀ = 0.27 µM). The experimental results are consistent with the computational observations. In silico ADME profiling also revealed good pharmacokinetic properties, indicating that bufadienolides A-F are lead compounds for further antiviral drug development. Taken together, our results support the hypothesis that bufadienolides are SARS-CoV-2 3CL^pro inhibitors and elucidate their mechanism of action, thereby laying the foundation for potential therapeutic advances against COVID-19.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566928","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}