Pub Date : 2026-01-08DOI: 10.1016/j.jmgm.2025.109272
Jorge Luis Valdés-Albuernes, Erbio Díaz-Pico, José Luis Velázquez-Libera, Julio Caballero
Ubiquitin-specific protease 7 (USP7) is a key regulator of protein homeostasis, playing critical roles in various cellular processes, including DNA damage response, immune signaling, and oncogenesis. Targeting USP7 with small-molecule inhibitors has emerged as a promising therapeutic strategy, particularly in the context of cancer and autoimmune diseases. Among the diverse scaffolds explored for USP7 inhibition, N-benzylpiperidinol (NBP) derivatives have shown notable potential due to their structural versatility and bioactivity. Computationally, it is possible to access models of complexes between these inhibitors and USP7 by utilizing the crystallographic structures of USP7 available in the Protein Data Bank. In a classical approach, models of NBPs can be obtained within a rigid USP7 structure. In this work, we report models of complexes between 58 NBPs and variable conformations of USP7 using a flexible docking protocol employing the novel CorrEA method. As part of this protocol, we obtained diverse USP7 structures through molecular dynamics (MD) and selected complex models with inhibitors based on their biological activities. Model quality was validated using LigRMSD and interaction fingerprints (IFP). The flexible treatment of USP7 enabled the capture of binding-site conformational changes. These changes are critical for explaining the activity differences among the studied compounds.
{"title":"Computational modeling of ubiquitin specific protease 7 (USP7) complexes with N-benzylpiperidinol derivatives incorporating binding site flexibility","authors":"Jorge Luis Valdés-Albuernes, Erbio Díaz-Pico, José Luis Velázquez-Libera, Julio Caballero","doi":"10.1016/j.jmgm.2025.109272","DOIUrl":"10.1016/j.jmgm.2025.109272","url":null,"abstract":"<div><div>Ubiquitin-specific protease 7 (USP7) is a key regulator of protein homeostasis, playing critical roles in various cellular processes, including DNA damage response, immune signaling, and oncogenesis. Targeting USP7 with small-molecule inhibitors has emerged as a promising therapeutic strategy, particularly in the context of cancer and autoimmune diseases. Among the diverse scaffolds explored for USP7 inhibition, <em>N</em>-benzylpiperidinol (NBP) derivatives have shown notable potential due to their structural versatility and bioactivity. Computationally, it is possible to access models of complexes between these inhibitors and USP7 by utilizing the crystallographic structures of USP7 available in the Protein Data Bank. In a classical approach, models of NBPs can be obtained within a rigid USP7 structure. In this work, we report models of complexes between 58 NBPs and variable conformations of USP7 using a flexible docking protocol employing the novel CorrEA method. As part of this protocol, we obtained diverse USP7 structures through molecular dynamics (MD) and selected complex models with inhibitors based on their biological activities. Model quality was validated using LigRMSD and interaction fingerprints (IFP). The flexible treatment of USP7 enabled the capture of binding-site conformational changes. These changes are critical for explaining the activity differences among the studied compounds.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109272"},"PeriodicalIF":3.0,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145928864","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}
Pub Date : 2026-01-03DOI: 10.1016/j.jmgm.2025.109271
Sampada Shelke , Rahul D. Jawarkar , Pravin N. Khatale , Umang Shah , Abdullah Yahya Abdullah Alzahrani , Abdul Samad , Sami A. Al-Hussain , Aamal A. Al-Mutairi , Magdi E.A. Zaki
This research introduces a comprehensive computational and experimental approach aimed at the systematic design of selective Histone Deacetylase 1 (HDAC1) inhibitors, which hold therapeutic promise for treating aggressive cancers. A comprehensive Quantitative Structure–Activity Relationship (QSAR) model was constructed utilizing 1168 experimentally validated HDAC1 inhibitors, incorporating molecular descriptors associated with hydrogen bonding, steric, and electronic properties. The validated model, with a R2 of 0.80 and a Q2 of 0.80, was utilized for the virtual screening of the ChemDiv HDAC library, successfully identifying high-potential hits. The leading compounds underwent receptor-based molecular docking with the HDAC1 crystal structure (PDB ID: 4BKX), which highlighted essential interactions such as zinc ion coordination and π–π stacking. Notably, compound 0356-0096 demonstrated a higher binding affinity than the reference inhibitor vorinostat. Molecular dynamics (MD) simulations conducted over a duration of 500 ns demonstrated the stability of the complex and a decrease in flexibility, as evidenced by analyses of Root Mean Square Deviation (RMSD) and Fluctuation (RMSF). The analysis of simulation trajectories through Principal Component Analysis (PCA) and the mapping of the Free Energy Landscape (FEL) revealed stable low-energy conformations that align with thermodynamically favorable binding conditions. The results of ADMET profiling demonstrated that the lead compounds exhibit good oral bioavailability, low toxicity, and favorable metabolic stability. Validation through in vitro methods using the MTT assay on MDA-MB-231 (triple-negative breast cancer) and A431 (epidermoid carcinoma) cell lines revealed significant, dose-dependent cytotoxic effects, with IC50 values of 2.7 μM and 91.6 nM, respectively. The computed Selectivity Index (SI) demonstrated a preferential cytotoxic effect on cancer cells in comparison to normal NRK kidney cells. This integrative QSAR–docking–MD–FEL–MTT approach effectively identified compound 0356–0096 as a potent and selective HDAC1 inhibitor. By combining predictive computational models with empirical validation, it provides a structured pathway for the preclinical development of targeted epigenetic cancer therapeutics.
{"title":"Integrated QSAR, molecular docking, and dynamics-based discovery of a potent selective HDAC1 inhibitor with therapeutic potential in aggressive cancers","authors":"Sampada Shelke , Rahul D. Jawarkar , Pravin N. Khatale , Umang Shah , Abdullah Yahya Abdullah Alzahrani , Abdul Samad , Sami A. Al-Hussain , Aamal A. Al-Mutairi , Magdi E.A. Zaki","doi":"10.1016/j.jmgm.2025.109271","DOIUrl":"10.1016/j.jmgm.2025.109271","url":null,"abstract":"<div><div>This research introduces a comprehensive computational and experimental approach aimed at the systematic design of selective Histone Deacetylase 1 (HDAC1) inhibitors, which hold therapeutic promise for treating aggressive cancers. A comprehensive Quantitative Structure–Activity Relationship (QSAR) model was constructed utilizing 1168 experimentally validated HDAC1 inhibitors, incorporating molecular descriptors associated with hydrogen bonding, steric, and electronic properties. The validated model, with a R<sup>2</sup> of 0.80 and a Q<sup>2</sup> of 0.80, was utilized for the virtual screening of the ChemDiv HDAC library, successfully identifying high-potential hits. The leading compounds underwent receptor-based molecular docking with the HDAC1 crystal structure (PDB ID: 4BKX), which highlighted essential interactions such as zinc ion coordination and π–π stacking. Notably, compound 0356-0096 demonstrated a higher binding affinity than the reference inhibitor vorinostat. Molecular dynamics (MD) simulations conducted over a duration of 500 ns demonstrated the stability of the complex and a decrease in flexibility, as evidenced by analyses of Root Mean Square Deviation (RMSD) and Fluctuation (RMSF). The analysis of simulation trajectories through Principal Component Analysis (PCA) and the mapping of the Free Energy Landscape (FEL) revealed stable low-energy conformations that align with thermodynamically favorable binding conditions. The results of ADMET profiling demonstrated that the lead compounds exhibit good oral bioavailability, low toxicity, and favorable metabolic stability. Validation through in vitro methods using the MTT assay on MDA-MB-231 (triple-negative breast cancer) and A431 (epidermoid carcinoma) cell lines revealed significant, dose-dependent cytotoxic effects, with IC<sub>50</sub> values of 2.7 μM and 91.6 nM, respectively. The computed Selectivity Index (SI) demonstrated a preferential cytotoxic effect on cancer cells in comparison to normal NRK kidney cells. This integrative QSAR–docking–MD–FEL–MTT approach effectively identified compound 0356–0096 as a potent and selective HDAC1 inhibitor. By combining predictive computational models with empirical validation, it provides a structured pathway for the preclinical development of targeted epigenetic cancer therapeutics.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109271"},"PeriodicalIF":3.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145924966","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}
Pub Date : 2026-01-02DOI: 10.1016/j.jmgm.2025.109270
Bhabesh Baro, Biplab Sarkar
The D dopamine receptor (DR), a member of the G protein-coupled receptor family, plays a critical role in neurophysiological processes and has emerged as a potential target for treating neurological disorders such as Parkinson’s disease. In this study, we employed computational approaches to investigate the molecular interactions of DR with dopamine and two key dopamine precursors: L-DOPA and droxidopa. Molecular docking was conducted to evaluate binding affinities and identify key receptor–ligand interactions, followed by molecular dynamics simulations to assess the stability and dynamic behavior of the complexes in a biological environment. MM-PBSA binding free energy calculations were used to further quantify the strength of ligand binding to DR.
{"title":"Evaluating the interactions of L-DOPA and droxidopa toward D3 dopamine receptor through computational study: A comparison with dopamine","authors":"Bhabesh Baro, Biplab Sarkar","doi":"10.1016/j.jmgm.2025.109270","DOIUrl":"10.1016/j.jmgm.2025.109270","url":null,"abstract":"<div><div>The D<span><math><msub><mrow></mrow><mrow><mn>3</mn></mrow></msub></math></span> dopamine receptor (D<span><math><msub><mrow></mrow><mrow><mn>3</mn></mrow></msub></math></span>R), a member of the G protein-coupled receptor family, plays a critical role in neurophysiological processes and has emerged as a potential target for treating neurological disorders such as Parkinson’s disease. In this study, we employed computational approaches to investigate the molecular interactions of D<span><math><msub><mrow></mrow><mrow><mn>3</mn></mrow></msub></math></span>R with dopamine and two key dopamine precursors: L-DOPA and droxidopa. Molecular docking was conducted to evaluate binding affinities and identify key receptor–ligand interactions, followed by molecular dynamics simulations to assess the stability and dynamic behavior of the complexes in a biological environment. MM-PBSA binding free energy calculations were used to further quantify the strength of ligand binding to D<span><math><msub><mrow></mrow><mrow><mn>3</mn></mrow></msub></math></span>R.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109270"},"PeriodicalIF":3.0,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145928866","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}
Pub Date : 2026-01-02DOI: 10.1016/j.jmgm.2025.109266
Dmitrii O. Shkil , Anastasia S. Fokina , Dariy T. Asainov , Elena V. Petersen , Andrey A. Ivashchenko , Philipp Y. Maximov
Cyclin-dependent kinases (CDKs) are pivotal regulators of the cell cycle and attractive therapeutic targets, particularly in breast cancer treatment. However, achieving selectivity among closely related CDKs, such as CDK2/CDK1, remains a significant challenge in drug discovery. In this study, we leverage molecular dynamics simulations and protein–ligand interaction analyses to uncover the structural and pharmacophoric determinants that drive selective inhibition of these kinases. By comparing known inhibitors and their contacts with CDK1 and CDK2, we identify critical pharmacophoric features essential for achieving target-specific selectivity. These findings provide valuable hypotheses into the design of next-generation CDK inhibitors with improved therapeutic profiles, addressing the pressing need for selective and effective cancer therapies.
{"title":"Selectivity analysis of CDK2 inhibitors via molecular dynamics of CDK1 and CDK2","authors":"Dmitrii O. Shkil , Anastasia S. Fokina , Dariy T. Asainov , Elena V. Petersen , Andrey A. Ivashchenko , Philipp Y. Maximov","doi":"10.1016/j.jmgm.2025.109266","DOIUrl":"10.1016/j.jmgm.2025.109266","url":null,"abstract":"<div><div>Cyclin-dependent kinases (CDKs) are pivotal regulators of the cell cycle and attractive therapeutic targets, particularly in breast cancer treatment. However, achieving selectivity among closely related CDKs, such as CDK2/CDK1, remains a significant challenge in drug discovery. In this study, we leverage molecular dynamics simulations and protein–ligand interaction analyses to uncover the structural and pharmacophoric determinants that drive selective inhibition of these kinases. By comparing known inhibitors and their contacts with CDK1 and CDK2, we identify critical pharmacophoric features essential for achieving target-specific selectivity. These findings provide valuable hypotheses into the design of next-generation CDK inhibitors with improved therapeutic profiles, addressing the pressing need for selective and effective cancer therapies.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"144 ","pages":"Article 109266"},"PeriodicalIF":3.0,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959558","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}
Pub Date : 2025-12-30DOI: 10.1016/j.jmgm.2025.109269
Z. Fadil , A. Jabar , M. Naziruddin Khan , S. Benyoussef , L. Bahmad , Abdulrahman A. Alsayyari , Chaitany Jayprakash Raorane , Seong-Cheol Kim
This study uses Monte Carlo simulations and density functional theory (DFT) to investigate the multifunctional properties of the Ti2MnCo compound. The alloy, which crystallizes in a stable cubic phase, exhibits metallic behavior and ferromagnetic ordering. The magnetism originates from the Mn and Co atoms, which display parallel spin alignment. The elastic properties indicate strong anisotropy and high rigidity. The Curie temperature (TC) is determined to be 77.36 K using DFT and 76.68 K using Monte Carlo simulations. Owing to its linear RCP behavior, Ti2MnCo appears to be a promising and versatile material for magnetic refrigeration and spintronic applications.
{"title":"Integrated DFT and Monte Carlo study of the multifunctional properties of Ti2MnCo Heusler alloy","authors":"Z. Fadil , A. Jabar , M. Naziruddin Khan , S. Benyoussef , L. Bahmad , Abdulrahman A. Alsayyari , Chaitany Jayprakash Raorane , Seong-Cheol Kim","doi":"10.1016/j.jmgm.2025.109269","DOIUrl":"10.1016/j.jmgm.2025.109269","url":null,"abstract":"<div><div>This study uses Monte Carlo simulations and density functional theory (<em>DFT</em>) to investigate the multifunctional properties of the <em>Ti</em><sub>2</sub><em>MnCo</em> compound. The alloy, which crystallizes in a stable cubic phase, exhibits metallic behavior and ferromagnetic ordering. The magnetism originates from the <em>Mn</em> and <em>Co</em> atoms, which display parallel spin alignment. The elastic properties indicate strong anisotropy and high rigidity. The Curie temperature (<em>T</em><sub><em>C</em></sub>) is determined to be 77.36 K using <em>DFT</em> and 76.68 K using Monte Carlo simulations<strong>.</strong> Owing to its linear <em>RCP</em> behavior, <em>Ti</em><sub>2</sub><em>MnCo</em> appears to be a promising and versatile material for magnetic refrigeration and spintronic applications.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109269"},"PeriodicalIF":3.0,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880520","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}
Pub Date : 2025-12-30DOI: 10.1016/j.jmgm.2025.109273
Kamal Kumar , Deepa Thakur , Ramesh Sharma , Abhishek K. Mishra
Carbon dioxide (CO2) capture is crucial to address both energy and environmental challenges. In this study, density functional theory (DFT) calculations are performed to investigate the adsorption behaviour of the CO2 molecule on pristine (P-XO2) and vacancy-defective (V-XO2) XO2 (X = Pd, Pt) monolayers (MLs). XO2 MLs exhibit a semiconducting natureand to study vacancies, we created X monovacancy (VX-XO2), O monovacancy (VO-XO2), and X-O divacancy (VX/O-XO2). Our findings reveal that CO2 adsorbs physically on PdO2 and PtO2 MLs with adsorption energies (Ead) of −18.67 and −19.83 kJ/mol, respectively, and minimal Bader charge transfer (−0.004 e− in both cases). Creation of Pd and O vacancies in PdO2 ML increases the magnitude of Ead for CO2, while the nature of adsorption remains the same. On the other hand, the CO2 molecule adsorbs chemically on VPd/O-PdO2 ML with an Ead of −55.47 kJ/mol and Bader charge transfer of 0.668e−. Also, the CO2 molecule bends after adsorption, which confirms its activation for further conversion. Similarly, CO2 adsorption on VO-PtO2 and VPt-PtO2 MLs falls in the category of physisorption due to Ead of −23.18 and −21.56 kJ/mol, respectively. Presence of Pt and O divacancy increases Ead to −29.89 kJ/mol. Thus, among all XO2 MLs, VPd/O-PdO2 ML appeared as a promising catalyst for activation and further electrochemical conversion of CO2.
{"title":"First-principles study of CO2 activation on pristine and defected XO2 (X= Pd, Pt) monolayers","authors":"Kamal Kumar , Deepa Thakur , Ramesh Sharma , Abhishek K. Mishra","doi":"10.1016/j.jmgm.2025.109273","DOIUrl":"10.1016/j.jmgm.2025.109273","url":null,"abstract":"<div><div>Carbon dioxide (CO<sub>2</sub>) capture is crucial to address both energy and environmental challenges. In this study, density functional theory (DFT) calculations are performed to investigate the adsorption behaviour of the CO<sub>2</sub> molecule on pristine (P-XO<sub>2</sub>) and vacancy-defective (V-XO<sub>2</sub>) XO<sub>2</sub> (X = Pd, Pt) monolayers (MLs). XO<sub>2</sub> MLs exhibit a semiconducting natureand to study vacancies, we created X monovacancy (V<sub>X</sub>-XO<sub>2</sub>), O monovacancy (V<sub>O</sub>-XO<sub>2</sub>), and X-O divacancy (V<sub>X/O</sub>-XO<sub>2</sub>). Our findings reveal that CO<sub>2</sub> adsorbs physically on PdO<sub>2</sub> and PtO<sub>2</sub> MLs with adsorption energies (E<sub>ad</sub>) of −18.67 and −19.83 kJ/mol, respectively, and minimal Bader charge transfer (−0.004 e<sup>−</sup> in both cases). Creation of Pd and O vacancies in PdO<sub>2</sub> ML increases the magnitude of E<sub>ad</sub> for CO<sub>2,</sub> while the nature of adsorption remains the same. On the other hand, the CO<sub>2</sub> molecule adsorbs chemically on V<sub>Pd/O</sub>-PdO<sub>2</sub> ML with an E<sub>ad</sub> of −55.47 kJ/mol and Bader charge transfer of 0.668e<sup>−</sup>. Also, the CO<sub>2</sub> molecule bends after adsorption, which confirms its activation for further conversion. Similarly, CO<sub>2</sub> adsorption on V<sub>O</sub>-PtO<sub>2</sub> and V<sub>Pt</sub>-PtO<sub>2</sub> MLs falls in the category of physisorption due to E<sub>ad</sub> of −23.18 and −21.56 kJ/mol, respectively. Presence of Pt and O divacancy increases E<sub>ad</sub> to −29.89 kJ/mol. Thus, among all XO<sub>2</sub> MLs, V<sub>Pd/O</sub>-PdO<sub>2</sub> ML appeared as a promising catalyst for activation and further electrochemical conversion of CO<sub>2</sub>.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109273"},"PeriodicalIF":3.0,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880432","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}
Pub Date : 2025-12-30DOI: 10.1016/j.jmgm.2025.109274
Elaheh Ahmadi, Maryam Anafcheh, Soode Amigh
The intrinsically slow kinetics of the oxygen reduction reaction (ORR) remains a major hurdle to the practical use of fuel cells. In this regard, we conducted a systematic theoretical exploration of ten dual-atom transition metal catalysts (Fe, Co, Ni, and Cu) supported on defective boron nitride to clarify the structure-activity relationship governing ORR performance. The evaluation of formation energies, stability, electronic structure, and catalytic properties indicates that dual-metal incorporation efficiently narrows the band gap of pristine BN and adjusts the d-band center, optimizing the adsorption and activation of oxygenated intermediates. Among the investigated catalysts, 2Cu-BN, CoCu-BN, and CuNi-BN have the lowest theoretical overpotentials of 0.64 V, 0.67 V, and 0.70 V, respectively. The 2Cu-BN catalyst exhibits a stable end-bridge adsorption configuration of O2, and the CoCu-BN and CuNi-BN catalysts show stable end-on adsorption configurations of O2 on top of cobalt and nickel centers, respectively. For the majority of the systems, the potential-determining step (PDS) is the transition of ∗OH → H2O, but the 2Cu-BN catalyst exhibits an alternate path with ∗O2 → ∗OOH as the PDS. Scaling relations and volcano plot analyses also confirm ΔG∗OH as a reliable descriptor of the ORR activity. Overall, these findings highlight the potential of 2D-BN-supported dual-atom catalysts as a promising next-generation fuel cell alternative that can substitute platinum efficiently and cost-effectively.
{"title":"DFT insights into synergistic interactions and ORR mechanisms of BN-supported dual-atom catalysts","authors":"Elaheh Ahmadi, Maryam Anafcheh, Soode Amigh","doi":"10.1016/j.jmgm.2025.109274","DOIUrl":"10.1016/j.jmgm.2025.109274","url":null,"abstract":"<div><div>The intrinsically slow kinetics of the oxygen reduction reaction (ORR) remains a major hurdle to the practical use of fuel cells. In this regard, we conducted a systematic theoretical exploration of ten dual-atom transition metal catalysts (Fe, Co, Ni, and Cu) supported on defective boron nitride to clarify the structure-activity relationship governing ORR performance. The evaluation of formation energies, stability, electronic structure, and catalytic properties indicates that dual-metal incorporation efficiently narrows the band gap of pristine BN and adjusts the d-band center, optimizing the adsorption and activation of oxygenated intermediates. Among the investigated catalysts, 2Cu-BN, CoCu-BN, and CuNi-BN have the lowest theoretical overpotentials of 0.64 V, 0.67 V, and 0.70 V, respectively. The 2Cu-BN catalyst exhibits a stable end-bridge adsorption configuration of O<sub>2</sub>, and the CoCu-BN and CuNi-BN catalysts show stable end-on adsorption configurations of O<sub>2</sub> on top of cobalt and nickel centers, respectively. For the majority of the systems, the potential-determining step (PDS) is the transition of ∗OH → H<sub>2</sub>O, but the 2Cu-BN catalyst exhibits an alternate path with ∗O<sub>2</sub> → ∗OOH as the PDS. Scaling relations and volcano plot analyses also confirm ΔG<sub>∗OH</sub> as a reliable descriptor of the ORR activity. Overall, these findings highlight the potential of 2D-BN-supported dual-atom catalysts as a promising next-generation fuel cell alternative that can substitute platinum efficiently and cost-effectively.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109274"},"PeriodicalIF":3.0,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900631","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}
Pub Date : 2025-12-27DOI: 10.1016/j.jmgm.2025.109268
Iverson Conrado Bezerra , Jéssika de Oliveira Viana , Jocelin Santa Rita Bisneto , Gabriel Gomes Cavalcante , João Gabriel Barbosa de Luna , Artur José da Silva , Karen Cacilda Weber , Giovanna Machado , José Luiz de Lima Filho , Priscila Gubert
Alzheimer's disease (AD) is characterized by progressive neurodegeneration, with aggregation of amyloid-β (Aβ1–42) playing a central role. Natural terpenes have emerged as promising therapeutic candidates due to their bioactivity. Here, we investigated caryophyllene and copaene interactions with Aβ1–42 via molecular docking, molecular dynamics simulations, and MM/PBSA calculations. Both terpenes bound effectively to distinct Aβ1–42 pockets, altering structural flexibility and disrupting aggregation-prone regions, mainly within the C-terminal and central hydrophobic domains. Inter-residue distance matrices showed increased separation between peptide segments, reducing compactness and potentially hindering β-sheet nucleation. Secondary structure analysis revealed decreased β-sheet content and preservation of α-helices, especially for caryophyllene in pocket 1 and copaene in pocket 2. Binding free energy analysis confirmed favorable thermodynamics dominated by hydrophobic interactions. These findings suggest caryophyllene and copaene interfere with early Aβ1-42 aggregation steps, supporting their potential as natural scaffolds for anti-amyloid drug development in AD.
{"title":"Computational insights into terpene-induced modulation of amyloid-β peptide (Aβ1–42) aggregation-favoring conformations","authors":"Iverson Conrado Bezerra , Jéssika de Oliveira Viana , Jocelin Santa Rita Bisneto , Gabriel Gomes Cavalcante , João Gabriel Barbosa de Luna , Artur José da Silva , Karen Cacilda Weber , Giovanna Machado , José Luiz de Lima Filho , Priscila Gubert","doi":"10.1016/j.jmgm.2025.109268","DOIUrl":"10.1016/j.jmgm.2025.109268","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is characterized by progressive neurodegeneration, with aggregation of amyloid-β (Aβ<sub>1–42</sub>) playing a central role. Natural terpenes have emerged as promising therapeutic candidates due to their bioactivity. Here, we investigated caryophyllene and copaene interactions with Aβ<sub>1–42</sub> via molecular docking, molecular dynamics simulations, and MM/PBSA calculations. Both terpenes bound effectively to distinct Aβ<sub>1–42</sub> pockets, altering structural flexibility and disrupting aggregation-prone regions, mainly within the C-terminal and central hydrophobic domains. Inter-residue distance matrices showed increased separation between peptide segments, reducing compactness and potentially hindering β-sheet nucleation. Secondary structure analysis revealed decreased β-sheet content and preservation of α-helices, especially for caryophyllene in pocket 1 and copaene in pocket 2. Binding free energy analysis confirmed favorable thermodynamics dominated by hydrophobic interactions. These findings suggest caryophyllene and copaene interfere with early Aβ<sub>1-42</sub> aggregation steps, supporting their potential as natural scaffolds for anti-amyloid drug development in AD.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109268"},"PeriodicalIF":3.0,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880433","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}
Pub Date : 2025-12-26DOI: 10.1016/j.jmgm.2025.109256
Marwah M.M. Madkhali , Halimah Alahmari , Safaa Alrehili , Arafat Toghan , Reda A. Haggam
The adsorption and sensing behavior of pristine and boron-doped C6N8 monolayers (BC6N7) toward CO, HF, and NO were systematically investigated using DFT, TD-DFT, NBO, NCI, and QTAIM analyses. The pristine C6N8 displayed a cohesive energy of −142.7 kcal mol−1 with a HOMO-LUMO gap of 2.94 eV, whereas boron doping reduced the gap to 1.55 eV and enhanced charge-transfer ability (ΔNmax = 5.09). Adsorption energies revealed strong binding for BC6N7@HF (−3.53 eV) and BC6N7@NO (−2.95 eV), both with fast recovery times. Electrical conductivity increased up to 2.47 × 109 A.m−2 upon NO adsorption. Dipole moment and polarizability reached maxima of 9.99 D and 149.97 a.u., respectively. Optical analyses showed notable redshifts, particularly C6N8@NO (λmax = 434 nm) and BC6N7@NO (442 nm). NBO analysis confirmed strong π→π∗ and n→π∗ interactions with stabilization energies up to 29.09 kcal mol−1, while QTAIM revealed the highest bond critical point density (ρ(r) = 0.271 a.u.) for C6N8@CO. These results highlight BC6N7, especially in HF and NO adsorption, as a promising candidate for fast, selective, and reusable toxic gas sensors.
{"title":"Boron-doped C6N8 monolayer as a promising nanosensor for ultrafast and selective detection of HF and NO: DFT and QTAIM study","authors":"Marwah M.M. Madkhali , Halimah Alahmari , Safaa Alrehili , Arafat Toghan , Reda A. Haggam","doi":"10.1016/j.jmgm.2025.109256","DOIUrl":"10.1016/j.jmgm.2025.109256","url":null,"abstract":"<div><div>The adsorption and sensing behavior of pristine and boron-doped C<sub>6</sub>N<sub>8</sub> monolayers (BC<sub>6</sub>N<sub>7</sub>) toward CO, HF, and NO were systematically investigated using DFT, TD-DFT, NBO, NCI, and QTAIM analyses. The pristine C<sub>6</sub>N<sub>8</sub> displayed a cohesive energy of −142.7 kcal mol<sup>−1</sup> with a HOMO-LUMO gap of 2.94 eV, whereas boron doping reduced the gap to 1.55 eV and enhanced charge-transfer ability (ΔNmax = 5.09). Adsorption energies revealed strong binding for BC6N7@HF (−3.53 eV) and BC6N7@NO (−2.95 eV), both with fast recovery times. Electrical conductivity increased up to 2.47 × 10<sup>9</sup> A.m<sup>−2</sup> upon NO adsorption. Dipole moment and polarizability reached maxima of 9.99 D and 149.97 a.u., respectively. Optical analyses showed notable redshifts, particularly C<sub>6</sub>N<sub>8</sub>@NO (<em>λ<sub>max</sub></em> = 434 nm) and BC<sub>6</sub>N<sub>7</sub>@NO (442 nm). NBO analysis confirmed strong π→π∗ and n→π∗ interactions with stabilization energies up to 29.09 kcal mol<sup>−1</sup>, while QTAIM revealed the highest bond critical point density (ρ(r) = 0.271 a.u.) for C6N8@CO. These results highlight BC<sub>6</sub>N<sub>7</sub>, especially in HF and NO adsorption, as a promising candidate for fast, selective, and reusable toxic gas sensors.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109256"},"PeriodicalIF":3.0,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145863075","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}
Pub Date : 2025-12-26DOI: 10.1016/j.jmgm.2025.109267
Abdullah M. Alnuqaydan
Cancer, more specifically, has a strong connection to aberrant kinase activity. Thereby, kinases serve as vital targets for the development of anti-cancer drugs. The ERK2 is a promising therapeutic option for advanced colon cancer treatment. This study seeks to evaluate the experimentally identified phytochemicals from Tamarix articulata for their inhibitory activity on colon cancer. The study employed molecular docking investigation to screen 222 derivatives against ERK2. The findings shortlisted 10 compounds based on the binding affinity score. 3/10 were further selected as the top 3 hits. The top 3 hits are Dicumarol (−9.7 kcal/mol), 2, 3, 9, 10-Tetrahydroxyberbine (−8.8 kcal/mol), and Nafenopin (−8.3 kcal/mol). The AZD0364 (−9.8 kcal/mol) was used as a reference/control in the present study. The compounds were further assessed for pharmacokinetics feature prediction; hence, all the compounds met the Lipinski Rule 5 parameters with no violations observed. The molecular dynamics (MD) simulation trajectory for the ERK2-ligand complexes yielded satisfactory results, characterized by a strong interaction and intermolecular conformational stability. The mean root mean square deviation (RMSD) noted for the top 3 complexes was <2 Å. The post-MD simulation analysis was performed to enhance and validate the efficacy of the complexes. The principal component analysis (PCA) analysis and hydrogen bonding assessment depicted 2, 3, 9, 10-Tetrahydroxyberbine as the most stable with no greater conformational variations, while the same complex created the most strong and stable bond with a total no-of frames 954, surpassing Dicumarol and Nefenopin. The unique salt bridges were observed in the novel ERK2-ligand complexes as per the comparative analysis with the control (Glu64-Lys147 and Glu43-Lys82, Glu297-Lys268, Glu203-Lys100, and Asp266-Lys268). The secondary structure studies plot depicted that all the ERK2-ligand complexes were stable. The MM-GBSA and MM-PBSA scores ranked Dicumarol as the top-notch compound (−67.44 kcal/mol and −68.66 kcal/mol). The WaterSwap considerably polishes our comprehensive simulation findings. Therefore, these findings offer a possible foundation for the exploration of inhibitors that target the ERK2 gene in vitro and in vivo, which might contribute to a landmark in cancer research.
{"title":"Unveiling Tamarix articulata phytochemicals as novel natural inhibitors of colon cancer: A holistic drug design and toxicological approach","authors":"Abdullah M. Alnuqaydan","doi":"10.1016/j.jmgm.2025.109267","DOIUrl":"10.1016/j.jmgm.2025.109267","url":null,"abstract":"<div><div>Cancer, more specifically, has a strong connection to aberrant kinase activity. Thereby, kinases serve as vital targets for the development of anti-cancer drugs. The ERK2 is a promising therapeutic option for advanced colon cancer treatment. This study seeks to evaluate the experimentally identified phytochemicals from <em>Tamarix articulata</em> for their inhibitory activity on colon cancer. The study employed molecular docking investigation to screen 222 derivatives against ERK2. The findings shortlisted 10 compounds based on the binding affinity score. 3/10 were further selected as the top 3 hits. The top 3 hits are Dicumarol (−9.7 kcal/mol), 2, 3, 9, 10-Tetrahydroxyberbine (−8.8 kcal/mol), and Nafenopin (−8.3 kcal/mol). The AZD0364 (−9.8 kcal/mol) was used as a reference/control in the present study. The compounds were further assessed for pharmacokinetics feature prediction; hence, all the compounds met the Lipinski Rule 5 parameters with no violations observed. The molecular dynamics (MD) simulation trajectory for the ERK2-ligand complexes yielded satisfactory results, characterized by a strong interaction and intermolecular conformational stability. The mean root mean square deviation (RMSD) noted for the top 3 complexes was <2 Å. The post-MD simulation analysis was performed to enhance and validate the efficacy of the complexes. The principal component analysis (PCA) analysis and hydrogen bonding assessment depicted 2, 3, 9, 10-Tetrahydroxyberbine as the most stable with no greater conformational variations, while the same complex created the most strong and stable bond with a total no-of frames 954, surpassing Dicumarol and Nefenopin. The unique salt bridges were observed in the novel ERK2-ligand complexes as per the comparative analysis with the control (Glu64-Lys147 and Glu43-Lys82, Glu297-Lys268, Glu203-Lys100, and Asp266-Lys268). The secondary structure studies plot depicted that all the ERK2-ligand complexes were stable. The MM-GBSA and MM-PBSA scores ranked Dicumarol as the top-notch compound (−67.44 kcal/mol and −68.66 kcal/mol). The WaterSwap considerably polishes our comprehensive simulation findings. Therefore, these findings offer a possible foundation for the exploration of inhibitors that target the ERK2 gene in vitro and in vivo, which might contribute to a landmark in cancer research.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109267"},"PeriodicalIF":3.0,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836531","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}
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