Journal of molecular graphics & modelling最新文献

{"title":"Discovery of a novel PI3Kα inhibitor for breast cancer therapy via virtual screening method, molecular dynamics simulation and biological evaluation","authors":"Thitiya Boonma ,&nbsp;Bodee Nutho ,&nbsp;Phongthon Kanjanasirirat ,&nbsp;Chananya Rajchakom ,&nbsp;Nadtanet Nunthaboot","doi":"10.1016/j.jmgm.2026.109289","DOIUrl":"10.1016/j.jmgm.2026.109289","url":null,"abstract":"<div><div>Phosphatidylinositol-4,5-bisphosphate 3-kinase alpha (PI3Kα) is a central signaling enzyme driving cell proliferation and growth in cancers including breast cancer. Selective inhibition of PI3Kα isoform has become a promising therapeutic approach. In this work, 2000 in-house natural compounds were virtually screened against the ATP-binding site of PI3Kα. Of these, 618 compounds were predicted to have acceptable drug-likeness, pharmacokinetic, and toxicity properties based on <em>in silico</em> ADMET screening. Docking analysis highlighted four candidates forming stable hydrogen bonds with key residues V851, S854, and Q859 in the PI3Kα binding pocket. Molecular dynamics simulations were then used to assess their structural features and dynamic stability. Hit 2 was found to form strong hydrogen bonds with E849 and V851 of the PI3Kα protein. MM/GBSA-based binding free energy analysis supported that Hit 2 possessed the most favorable binding affinity to PI3Kα among the identified candidates. <em>In vitro</em> cytotoxicity assays were then performed in MCF-7 and MDA-MB-231 breast cancer cell lines, with alpelisib as a reference compound. Hit 2 reduced cell viability in both cell lines, but its effect was particularly pronounced in MDA-MB-231 cells, a model of triple-negative breast cancer (TNBC). These results suggest that Hit 2 represents a promising natural scaffold for further design and development in breast cancer therapy, with particular relevance for aggressive TNBC.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109289"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145980548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantum chemical investigations of electronic properties, chemical reactivity, FTIR, thermodynamic behaviors and biological activity for some novel quercetin derivatives","authors":"Noha A. Saleh ,&nbsp;Bushra M.D. Mansoor ,&nbsp;A. Alkhaldi ,&nbsp;Munirah A. Almessiere","doi":"10.1016/j.jmgm.2026.109298","DOIUrl":"10.1016/j.jmgm.2026.109298","url":null,"abstract":"<div><div>Quercetin is a crucial natural bioactive substance present in many plants offering numerous health benefits. This computational study uses DFT calculations at the B3LYP/6-31G∗∗ level to computationally investigate novel quercetin derivatives modified by a tetra-amino acid sequence (Ser-Gly-Lys-Arg) in various structural forms including α-amino acids, β-amino acids, mixed-amino acids, and ketoacid. These modifications aim to improve the physicochemical and biological properties of quercetin providing a helpful framework for producing more potent bioactive compounds. Frontier molecular orbital analysis, molecular electrostatic potential mapping and reactivity indices reveal that β-amino acid and ketoacid derivatives exhibit enhanced electronic reactivity and thermodynamic stability relative to native quercetin. In addition, quantitative structure activity relationship (QSAR) descriptors and ADMET predictions are employed as comparative indicators to assess trends in polarity, solubility, and molecular permeability among the investigated compounds. The results highlight how peptide conjugation modulates the electronic and physicochemical properties of quercetin providing a rational computational basis for the future design of quercetin based peptidomimetic systems for further experimental investigation.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109298"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational assessment of clerodane-type furano-diterpenoids from Tinospora crispa: A potential source for anticancer lead compounds","authors":"Juhaer Anjum ,&nbsp;Sabiha Enam Spriha ,&nbsp;Mir Sabit Hossain ,&nbsp;S.M. Abdur Rahman","doi":"10.1016/j.jmgm.2026.109312","DOIUrl":"10.1016/j.jmgm.2026.109312","url":null,"abstract":"<div><div><em>Tinospora crispa,</em> a plant with widespread use in ethnomedicine, has several extracts as well as phytoconstituents that have been reported to possess anticancer properties. Clerodane-type furano-diterpenoids from this genus of plants show promise as anticancer agents, although only a few of these have been assayed <em>in vitro.</em> 38 clerodane-type furano-diterpenoids from <em>T. crispa</em> were assayed computationally against 13 common anticancer macromolecular targets. The assayed ligand library displayed higher binding affinities than the respective controls in six of the thirteen anticancer macromolecular targets. Binding affinity values that were higher than the respective controls were obtained for two ligands against BRCA1, for four against CDK9/Cyclin T1, for two against C-ROS1, for thirty-seven against EGFR, for three against MEK 1-kinase, and for one against STAT3. Many of these ligands displayed greater binding affinity values than the respective controls against multiple macromolecules. Notable among these are tinocrispide (against BRCA1, C-ROS1, EGFR and MEK1), tinosporol C (against CDK9/Cyclin T1 and MEK1-kinase), crispene E (against BRCA1 and CDK9/Cyclin T1) and (5R,6R,8S,9R,10R,12S)-15,16-Epoxy-2-oxo-6-O-(β-D-glucopyranosyl)-cleroda-3,13(16),14-trien-17,12-olid-18-oic acid methyl ester (against BRCA1 and EGFR). The top scoring compounds of each macromolecule were subjected to molecular dynamics simulations, and the obtained protein-ligand complexes were observed to be stable for all macromolecules except EGFR. The ligand library was mostly predicted to be soluble, but GI absorption was predicted to vary. A few were predicted to be carcinogenic, immunotoxic, and/or cytotoxic. Overall, the clerodane-type furano-diterpenoids from <em>T. crispa</em> show encouraging results in <em>in-silico</em> studies and may be considered for further modification and lead development.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109312"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms of aquaporin 1 inhibition by Bacopaside I and Bacopaside II: Insights from molecular dynamics simulations","authors":"Mingyu Wei ,&nbsp;Zien Yu ,&nbsp;Chi Huang ,&nbsp;Shuwei Han ,&nbsp;Sitian Zhou ,&nbsp;Ting Wang ,&nbsp;Shibin Chang ,&nbsp;Xiaoying Chen ,&nbsp;Feisheng Zhong ,&nbsp;Shaojie Ma","doi":"10.1016/j.jmgm.2026.109302","DOIUrl":"10.1016/j.jmgm.2026.109302","url":null,"abstract":"<div><div>Aquaporin-1 (AQP1),a key water channel protein, is aberrantly overexpressed in multiple malignancies, rendering it a compelling therapeutic target. The natural products Bacopaside I and Bacopaside II have demonstrated inhibitory activity against AQP1, yet their molecular mechanisms remain elusive. To elucidate the atomic basis of this inhibition, we employed a comprehensive computational approach combining molecular docking, molecular dynamics (MD) simulations, and extensive Gaussian accelerated molecular dynamics (GaMD) simulations with molecular mechanics generalized Born surface area (MM/GBSA) analysis. Our simulations indicate that both compounds exert spatial effects by occupying pore space, physically blocking channels, and forming van der Waals interactions with hydrophobic amino acids. In addition, ligands form hydrogen bonds with amino acids near these regions, resulting in narrower channels compared to other parts of AQP1. MM/GBSA calculations indicate that Bacopaside Ⅱ (Δ<em>G</em>_bind = −34.48 kcal/mol) has a higher binding affinity than Bacopaside I (Δ<em>G</em>_bind = −31.76 kcal/mol). Energy decomposition analysis identifies key interacting residues Pro171, Ile174, and Ala66 that anchor the inhibitors. Although both ligands induce subtle constriction of the channel pores, Bacopaside II establishes a more persistent hydrogen bonding network, underscoring its unique energetic contribution to the inhibition profile. Overall, these findings provide a detailed mechanistic blueprint for AQP1 inhibition by Bacopasides and offer a structural framework for the rational design of next-generation AQP1-targeted anticancer therapies.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109302"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing disulfiram for ALDH-positive NSCLC: Network-based inhibition of EGFR, COX-2, and MAPK1","authors":"Zhengdong Liu,&nbsp;Xiang Yang,&nbsp;Ji Zhang","doi":"10.1016/j.jmgm.2026.109313","DOIUrl":"10.1016/j.jmgm.2026.109313","url":null,"abstract":"<div><div>The clinical management of non-small cell lung cancer (NSCLC) is of major challenge due to the contribution of ALDH-positive non-small cell lung cancer to tumor aggressiveness, metastasis, and resistance to therapy. The FDA-approved alcohol aversion agent disulfiram (DSF) has been shown to be promising in preclinical models aiming to treat tumor in the animal model but its efficacy in vivo is limited by poorly understood molecular targets in ALDH + NSCLC. Our hypothesis is that DSF will act on important nodes within the oncogenic (EGFR/MAPK), inflammatory (COX-2) and redox pathways which maintain ALDH + stemness. To evaluate this, network pharmacology was used and determined 137 common targets to exist between DSF and NSCLC-related genes. Analysis of protein-protein interaction has identified the following central hubs: EGFR, PTGS2 (COX-2), and MAPK1. These targets were found to bind DSF with very high affinity (7.45 -6.15 -6.65 kcal/mol, respectively) in comparison to reference inhibitors (Erlotinib, Celecoxib, Sorafenib). The RMSD values remaining below 2.1 Å, MMGBSA analysis, and consistent energy gyration profiles, supporting the stability of the DSF-target complexes. DSF (IC50 = 2.5 μM) experimentally caused a significant decrease in phosphorylation of EGFR, ERK1 (MAPK1) and COX-2 in NSCLC cells. The article presents mechanistic support to the multi-target effect of DSF in ALDH + NSCLC through inhibition of EGFR, COX-2, and MAPK1, potent agents of stemness and resistance to drugs. It is believed that the reuse of DSF would be effective in treating NSCLC therapeutic resistance and promote its use in practice.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109313"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-principles calculations of structural, electronic, optical, and catalytic properties in gallium nitride-substituted iron carbonyl complexes: [Fe(CO)4(GaN)] and [Fe(CO)3(GaN)2]","authors":"D. Bavya ,&nbsp;S. Subashchandrabose ,&nbsp;P. Parthiban ,&nbsp;A. Nandhakumar","doi":"10.1016/j.jmgm.2026.109320","DOIUrl":"10.1016/j.jmgm.2026.109320","url":null,"abstract":"<div><div>Density functional theory (DFT) calculations at the B3LYP with LANL2DZ, SDD and 6-31G+(d) basis set provide comprehensive insights into the structural dynamics, bonding interactions, bond orders and nonlinear optical (NLO) response of novel iron-gallium carbonyl complexes [Fe(CO)₄(GaN)] (<strong>C1</strong>) and [Fe(CO)₃(GaN)₂] (<strong>C2</strong>). Geometry optimizations and bond orders confirm distorted pseudo-octahedral Fe centers with contracted Fe-CO bonds (1.75-1.81 Å) and typical Fe-Ga (2.31-2.36 Å) and Ga-N (1.81-1.85 Å) metrics, accompanied by near-linear Fe-C-O angles favouring optimal π-backdonation. Vibrational analysis reveals characteristic CO stretches that blue shifted upon bis(GaN) substitution, coupled Ga-N modes, and softened Fe-Ga scaffold vibrations indicative of enhanced mechanical coupling. Frontier molecular orbital (FMO) analysis shows a wider HOMO-LUMO gap in <strong>C1</strong> (1.43 eV) versus <strong>C2</strong> (1.03 eV), with delocalized π-type manifolds dominated by Fe. The <span><math><mrow><msub><mi>t</mi><mrow><mn>2</mn><mi>g</mi></mrow></msub></mrow></math></span> (d)-like HOMOs and antibonding π∗ LUMOs incorporating Ga-N contributions, correlating with lower chemical hardness (η = 0.515 eV) and higher electrophilicity (ω = 4.245 eV) for the softer, more reactive <strong>C2</strong>. Natural bond orbital (NBO) dissection quantifies strong donor-acceptor delocalizations (E² &gt; 20 kcal mol⁻¹) across Fe-CO, Fe-Ga, and Ga-N linkages, with bis (GaN) coordination amplifying intramolecular charge transfer and modulating back bonding. Notably, finite-field hyperpolarizability calculations yield β₀ values of 3.124 × 10⁻³⁰ esu (1) and 4.769 × 10⁻³⁰ esu (2), surpassing urea and highlighting 2 as a superior second-order NLO pore due to extended conjugation and push-pull asymmetry. These findings establish Ga-N fragments as isolobal CO mimics that systematically tune stability, reactivity, and NLO efficiency in low-valent iron carbonyls, paving the way for rational design of organometallic materials in optoelectronics and catalysis.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109320"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146180800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Theoretical insights into adsorption behaviors and 17O nuclear magnetic resonance investigations of water clusters over xylitol-decorated hexagonal boron nitride","authors":"Songjin Zheng ,&nbsp;Wei Shen ,&nbsp;Di Kang ,&nbsp;Haitao Wang ,&nbsp;Yifan Bu ,&nbsp;Ningyang Mao ,&nbsp;Yihan Zhang ,&nbsp;Tao Wang ,&nbsp;Li Xu ,&nbsp;Henan Li ,&nbsp;Hongping Li","doi":"10.1016/j.jmgm.2026.109318","DOIUrl":"10.1016/j.jmgm.2026.109318","url":null,"abstract":"<div><div>The precise modulation of water cluster behavior on material surfaces is critical for numerous technological applications but remains challenging due to the complexity of hydrogen-bonding interactions. This study presents a comprehensive theoretical investigation into the adsorption structures, interaction energetics, and ¹⁷O nuclear magnetic resonance (NMR) spectroscopic signatures of water clusters on both pristine and xylitol-decorated hexagonal boron nitride (h-BN-xyl) surfaces, using density functional theory (DFT) calculations. Results demonstrate that xylitol functionalization drastically enhances the adsorption capacity of h-BN, with interaction energies increasing up to threefold compared to pristine h-BN, which is attributed to the formation of multiple bidirectional hydrogen bonds between the hydroxyl groups of xylitol and the water clusters. Topological and electrostatic potential analyses confirm the introduction of strong, electron-rich adsorption sites on h-BN-xyl. Crucially, ¹⁷O NMR chemical shifts exhibit systematic downfield displacements upon adsorption on h-BN-xyl, indicating a deshielding effect due to reduced electron density on oxygen atoms and a more complex hydrogen-bonding network. This work establishes a robust structure-spectroscopy relationship, highlighting the dual utility of DFT and NMR simulations in deciphering interfacial water dynamics and providing predictive design principles for advanced functional materials in fields such as catalysis, sensing, and environmental technology.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109318"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Green chemistry strategies for CO2 valorization: Impact of substituents, solvents and catalysts on the cycloaddition of CO2 with epoxides forming cyclic carbonates","authors":"Imen Ferchichi ,&nbsp;Frédéric Guégan ,&nbsp;Muneerah Mogren Al-Mogren ,&nbsp;Majdi Hochlaf ,&nbsp;Youssef Arfaoui","doi":"10.1016/j.jmgm.2026.109306","DOIUrl":"10.1016/j.jmgm.2026.109306","url":null,"abstract":"<div><div>A theoretical study of the reaction forming a cyclic carbonate from the cycloaddition of CO₂ with a typical substituted epoxide, was carried out using first principles methodologies. As epoxide, we considered <em>trans</em> 1-(4-methoxyphenyl)-2-methoxy epoxyethane, exhibiting an optimal reactivity for cycloaddition with CO₂. We found that this reaction exhibits a high energy barrier in the gas phase, thus requiring an activation method. We also investigated the role of various substituted epoxides (mono- and disubstituted) and solvent types, including nonpolar, polar protic, and polar aprotic solvents. Our findings revealed a preference for polar protic solvents, particularly water. Besides, we used catalysts, including Lewis bases and Lewis acids, to selectively favor one reaction pathway over the other. In sum, this study provides deep insights into the factors influencing the reactivity of this cycloaddition and identifies the most suitable solvents and catalysts to promote the reaction, with potential implications for the development of more efficient CO₂ valorization processes.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109306"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Significantly improved optoelectronic properties of WWC-103 engineered for efficient perovskite solar cells: A DFT approach","authors":"Umer Yaqoob ,&nbsp;Sidra Rafiq ,&nbsp;Muhammad Zohaib Sabir ,&nbsp;Ali Raza Ayub ,&nbsp;Salba ,&nbsp;Makhvela Anwer ,&nbsp;Asma Parveen","doi":"10.1016/j.jmgm.2026.109300","DOIUrl":"10.1016/j.jmgm.2026.109300","url":null,"abstract":"<div><div>Incorporating hole-transporting materials (HTMs) with optimal hole mobility and solution-processability is crucial for modifying effective materials of solar cells. In this investigation, we designed eight molecules with a D-A-type arrangement. The modified hole-transporting materials were studied using a quantum computation approach using density functional theory to found structural properties related to the electrochemical, charge transfer, quantum physical, solubility, and photovoltaic properties. The outcomes reveal that accepting fragments manifested hole-transport materials appropriate band alignment with deeper <span><math><mrow><msub><mi>E</mi><mrow><mi>H</mi><mi>O</mi><mi>M</mi><mi>O</mi></mrow></msub></mrow></math></span> levels (ranging from −6.50 to −6.76 eV), higher absorption coefficients, remarkable solution processibility, and hole mobility with low exciton binding energy. These features revealed a higher photocurrent-generating ability, as estimated from transition density calculations across the molecular frameworks, a low charge-coupling estimated by the lower reorganization energy, and robust exciton dissociation. These notable outcomes unveiled that modified molecules are comparatively better than WWC-103 as HTMs for fabricating efficient material in the photovoltaic industry.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109300"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based computational assessment of Bacopa monnieri-derived compounds as potential dual target anti-seizure medications: An integrated docking and molecular dynamics simulation approach","authors":"Uttara Bakshi,&nbsp;Ashis Datta","doi":"10.1016/j.jmgm.2026.109309","DOIUrl":"10.1016/j.jmgm.2026.109309","url":null,"abstract":"<div><div>Epilepsy remains a debilitating neurological disorder affecting approximately 50 million individuals worldwide. Current Anti-seizure medications (ASM) targeting Synaptic Vesicle Protein 2A (SV2A), such as levetiracetam, exhibit variable efficacy and adverse effect profiles, necessitating exploration of novel therapeutic approaches. This study investigates <em>Bacopa monnieri</em>-derived compounds as potential dual inhibitors of SV2A and Carbonic Anhydrase II (CA-II), two mechanistically distinct targets implicated in seizure pathophysiology. An integrated computational workflow comprising ADMET profiling, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations was implemented to evaluate selected phytoconstituents. ADMET analysis revealed favourable pharmacokinetic parameters for several compounds, particularly Ebelin Lactone and Jujubogenin, with superior blood-brain barrier permeability (BBB &gt;0.9) and human intestinal absorption (&gt;95 %) compared to reference drugs. Molecular docking identified compelling binding affinities, with Ebelin Lactone (−11.2 kcal/mol) and Jujubogenin (−10.9 kcal/mol) exhibiting stronger interactions with SV2A than brivaracetam (−6.8 kcal/mol). Similarly, these compounds demonstrated robust binding to CA-II (−8.4 and −8.7 kcal/mol, respectively). Protein-ligand interaction profiler analysis elucidated key stabilizing interactions, including hydrogen bonds with Thr199 and His64 in CA-II and hydrophobic contacts within the SV2A binding pocket. MD simulations confirmed structural stability of the protein-ligand complexes, evidenced by equilibrated RMSD trajectories (0.2–0.3 nm). MM-GBSA calculations substantiated the thermodynamic favourability of these interactions, with binding free energies for top candidates significantly exceeding reference compounds. These findings establish an in silico framework for prioritizing <em>Bacopa monnieri</em> phytoconstituents as computationally predicted dual-target candidates, highlighting their potential relevance for seizure management, with the possibility of improved efficacy through simultaneous modulation of distinct pathophysiological mechanisms. All findings are based solely on in silico analyses and require experimental validation.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109309"},"PeriodicalIF":3.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}