Pub Date : 2026-03-01Epub 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":"2026-03-01","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 : 2026-03-01Epub Date: 2025-12-18DOI: 10.1016/j.jmgm.2025.109262
Anjana C. Lalu , Bristow Ben Joseph , Varun T.K., Amritha Thaikkad, Leona Dcunha, Rajesh Raju, Abhithaj Jayanandan
Leukemia is a type of blood cancer that occurs when abnormal white blood cells grow too quickly. This uncontrolled growth begins in the bone marrow, where blood cells are produced. Leukemia remains a major health concern due to its high incidence and difficult prognosis. It is the most common type of cancer in children and ranks among the top 15 most prevalent cancers in adults, as reported by the World Health Organization. Several BRD4 inhibitors have shown promising potential as treatments for leukemia. These molecules function by blocking BRD4's interaction with acetylated histones, specifically targeting key amino acid residue ASN140. By disrupting this binding, they offer a potentially more effective therapeutic approach in combating leukemia. Current cancer treatments, such as chemotherapy and targeted therapies like JQ1, frequently come with side effects and toxicity, which highlights the need for safer alternatives. In our study, we explored plant-derived natural compounds that might offer anticancer benefits while being easier on the body. Using advanced techniques like pharmacophore-based virtual screening and ADMET analysis, we identify potential candidates. Molecular docking and dynamics simulations further revealed strong and stable interactions between BRD4 protein and these compounds. Notably, Calyxins C had the best interaction profile, with a docking score of −12.756 kcal/mol and a binding free energy of −85.32 kcal/mol. For Calyxins A, the binding free energy was −72.53 kcal/mol with a docking score of −10.132 kcal/mol, while for Deoxycalyxin A, it was −73.03 kcal/mol with a docking score of −10.162 kcal/mol. Our research indicates that these natural compounds, Calyxins C, Calyxins A, and Deoxyocalyxin A, exhibit higher stability and favorable interaction profiles, which could be effective and less toxic drug leads for leukemia treatment, paving the way for future experimental validation and clinical studies.
{"title":"Pharmacoinformatic discovery of plant-derived BRD4 inhibitors as potential therapeutic agents for leukemia","authors":"Anjana C. Lalu , Bristow Ben Joseph , Varun T.K., Amritha Thaikkad, Leona Dcunha, Rajesh Raju, Abhithaj Jayanandan","doi":"10.1016/j.jmgm.2025.109262","DOIUrl":"10.1016/j.jmgm.2025.109262","url":null,"abstract":"<div><div>Leukemia is a type of blood cancer that occurs when abnormal white blood cells grow too quickly. This uncontrolled growth begins in the bone marrow, where blood cells are produced. Leukemia remains a major health concern due to its high incidence and difficult prognosis. It is the most common type of cancer in children and ranks among the top 15 most prevalent cancers in adults, as reported by the World Health Organization. Several BRD4 inhibitors have shown promising potential as treatments for leukemia. These molecules function by blocking BRD4's interaction with acetylated histones, specifically targeting key amino acid residue ASN140. By disrupting this binding, they offer a potentially more effective therapeutic approach in combating leukemia. Current cancer treatments, such as chemotherapy and targeted therapies like JQ1, frequently come with side effects and toxicity, which highlights the need for safer alternatives. In our study, we explored plant-derived natural compounds that might offer anticancer benefits while being easier on the body. Using advanced techniques like pharmacophore-based virtual screening and ADMET analysis, we identify potential candidates. Molecular docking and dynamics simulations further revealed strong and stable interactions between BRD4 protein and these compounds. Notably, Calyxins C had the best interaction profile, with a docking score of −12.756 kcal/mol and a binding free energy of −85.32 kcal/mol. For Calyxins A, the binding free energy was −72.53 kcal/mol with a docking score of −10.132 kcal/mol, while for Deoxycalyxin A, it was −73.03 kcal/mol with a docking score of −10.162 kcal/mol. Our research indicates that these natural compounds, Calyxins C, Calyxins A, and Deoxyocalyxin A, exhibit higher stability and favorable interaction profiles, which could be effective and less toxic drug leads for leukemia treatment, paving the way for future experimental validation and clinical studies.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109262"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827822","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 : 2026-03-01Epub Date: 2025-12-12DOI: 10.1016/j.jmgm.2025.109254
G. Dodero , E. Noseda Grau , A. Díaz Compañy , G. Román , S. Simonetti
The adsorption of hydrochlorothiazide and aspirin drugs onto a phosphorus (P) -magnesium (Mg) -doped (5,3) single-walled carbon nanotube (SWCNT) is investigated by density-functional theory (DFT) calculations using the Vienna Ab initio Simulation Package (VASP). The optimization of different structures indicates that the hydrochlorothiazide drug is stronger adsorbed than aspirin onto (5,3) SWCNT-P-Mg, affecting de release kinetics of the drugs. The results manifest the importance of the selected dopant atoms on the modification of the material surface in order to change the adsorption properties and the release conditions. We corroborate the results by means of electronic structure, density of states (DOS), frontier orbitals, and molecular electrostatic potential analysis.
利用维也纳从头算模拟包（VASP），通过密度泛函理论（DFT）计算，研究了磷(P) -镁（Mg）掺杂（5,3）单壁碳纳米管（SWCNT）对氢氯噻嗪和阿司匹林药物的吸附。不同结构的优化表明，氢氯噻嗪类药物比阿司匹林更强地吸附在（5,3）swcnts - p - mg上，影响药物的释放动力学。结果表明，掺杂原子的选择对于改变材料表面的吸附性能和释放条件具有重要意义。我们通过电子结构、态密度（DOS）、前沿轨道和分子静电势分析证实了结果。
{"title":"(5,3) SWCNT-doping phosphorus-magnesium: Difference in adsorption of cardiovascular drugs","authors":"G. Dodero , E. Noseda Grau , A. Díaz Compañy , G. Román , S. Simonetti","doi":"10.1016/j.jmgm.2025.109254","DOIUrl":"10.1016/j.jmgm.2025.109254","url":null,"abstract":"<div><div>The adsorption of hydrochlorothiazide and aspirin drugs onto a phosphorus (P) -magnesium (Mg) -doped (5,3) single-walled carbon nanotube (SWCNT) is investigated by density-functional theory (DFT) calculations using the Vienna Ab initio Simulation Package (VASP). The optimization of different structures indicates that the hydrochlorothiazide drug is stronger adsorbed than aspirin onto (5,3) SWCNT-P-Mg, affecting de release kinetics of the drugs. The results manifest the importance of the selected dopant atoms on the modification of the material surface in order to change the adsorption properties and the release conditions. We corroborate the results by means of electronic structure, density of states (DOS), frontier orbitals, and molecular electrostatic potential analysis.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109254"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756839","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 : 2026-03-01Epub 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":"2026-03-01","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 : 2026-03-01Epub 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":"2026-03-01","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 : 2026-03-01Epub Date: 2025-12-01DOI: 10.1016/j.jmgm.2025.109247
Mousa Soleymani , Mahdieh Goudarzi
This work investigates theoretically the activation and directing effects in a fluorinated allenic system, 1-(5,5-difluoropenta-3,4-dienyl)benzene (FPB), during a Cu+-catalyzed cycloaddition reaction with phenyl nitrile oxide (NO). The FPB…Cu+ interactions were studied and it was found coordination of Cu+ ion to the central carbon atom of the allenic system and a cation-π interaction in the most stable complex. Four potential possible reaction paths were considered between FPB and NO and the computational results corroborated the experimental findings, indicating that the formation of CA-2 is favored in uncatalyzed reaction, whereas CA-3 formation is preferred in catalyzed one. The calculated energy difference between the most stable and unstable TS is about 32 kJ/mol for the uncatalyzed system, a value that increases to 192 kJ/mol under catalysis. Furthermore, the computed activation Gibbs free energy for TS-2 (the most favorable transition state in uncatalyzed reaction) is 101.03 kJ/mol and that for TS-3-cat (the most favorable TS in catalyzed reaction) is 92.02 kJ/mol. Consequently, the catalyst is shown to be effective not only in decreasing the activation barrier but also in controlling the regioselectivity of the reaction by increasing the difference between the energy surfaces of TSs. The regioselectivity was rationalized through Natural Bond Orbital NBO (based on values resulted from perturbation theory) and Independent Gradient Model based on Hirshfeld partition (IGMH) analyses. Finally, application of the Electron Localization Function (ELF) analysis revealed the molecular mechanism to be a two-stage one-step mechanism in both cases.
{"title":"Fluorine-activated and -directed allene cycloadditions with nitrile oxide: Exploration of selectivities, reactivities, energetic aspects, and molecular mechanism","authors":"Mousa Soleymani , Mahdieh Goudarzi","doi":"10.1016/j.jmgm.2025.109247","DOIUrl":"10.1016/j.jmgm.2025.109247","url":null,"abstract":"<div><div>This work investigates theoretically the activation and directing effects in a fluorinated allenic system, 1-(5,5-difluoropenta-3,4-dienyl)benzene (<strong>FPB</strong>), during a Cu<sup>+</sup>-catalyzed cycloaddition reaction with phenyl nitrile oxide (<strong>NO</strong>). The <strong>FPB</strong>…Cu<sup>+</sup> interactions were studied and it was found coordination of Cu<sup>+</sup> ion to the central carbon atom of the allenic system and a cation-π interaction in the most stable complex. Four potential possible reaction paths were considered between <strong>FPB</strong> and <strong>NO</strong> and the computational results corroborated the experimental findings, indicating that the formation of <strong>CA-2</strong> is favored in uncatalyzed reaction, whereas <strong>CA-3</strong> formation is preferred in catalyzed one. The calculated energy difference between the most stable and unstable TS is about 32 kJ/mol for the uncatalyzed system, a value that increases to 192 kJ/mol under catalysis. Furthermore, the computed activation Gibbs free energy for <strong>TS-2</strong> (the most favorable transition state in uncatalyzed reaction) is 101.03 kJ/mol and that for <strong>TS-3-cat</strong> (the most favorable TS in catalyzed reaction) is 92.02 kJ/mol. Consequently, the catalyst is shown to be effective not only in decreasing the activation barrier but also in controlling the regioselectivity of the reaction by increasing the difference between the energy surfaces of TSs. The regioselectivity was rationalized through Natural Bond Orbital NBO (based on <span><math><mrow><msubsup><mi>E</mi><mrow><mi>i</mi><mo>→</mo><mi>j</mi></mrow><mrow><mo>(</mo><mn>2</mn><mo>)</mo></mrow></msubsup></mrow></math></span> values resulted from <span><math><mrow><msup><mi>E</mi><mrow><mo>(</mo><mn>2</mn><mo>)</mo></mrow></msup></mrow></math></span> perturbation theory) and Independent Gradient Model based on Hirshfeld partition (IGMH) analyses. Finally, application of the Electron Localization Function (ELF) analysis revealed the molecular mechanism to be a <em>two-stage one-step</em> mechanism in both cases.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109247"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145677679","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 : 2026-03-01Epub Date: 2025-12-04DOI: 10.1016/j.jmgm.2025.109246
Saurabh Gupta, Yogita Bansal
Dysregulation of p38α MAP kinase (MAPK14) increases the production of pro-inflammatory cytokines, causing pathogenesis of inflammatory, oncological, and neurodegenerative diseases. Till date, no orally effective p38α MAPK inhibitor exists in clinics, which may be due to poor selectivity and off-target effects. This emphasizes the urgent need for the design of potential p38α MAPK inhibitors. In this study, SMILES-based 2D-QSAR and field-point-based 3D QSAR models were developed to guide the design of novel p38α MAPK inhibitors. A dataset of 207 molecules was used to developed 2D-QSAR models via Monte Carlo optimization. Among fifteen models, Split-3 of model 14 exhibited highest statistical performance and was identified as the best model. Structural fragments that either enhance or hinder activity were identified. Subsequently for 3D-QSAR approach, a pharmacophoric template was generated and employed to align dataset. This aligned dataset was utilized to developed 3D-QSAR and a 5-component model showed superior predictivity and provided SAR insights. Based on these insights, a virtual library of 14,040 compounds was designed and screened using in silico workflow such as Lipinski's Rule of Five, predicted pIC50, molecular docking, electrostatic complementarity, molecular dynamics simulations, MM/GBSA, WaterSwap, and ADMET predictions. From this virtual screening, compound P38S002073 emerged as the most promising lead candidate. Overall, this integrative approach provides important structural insights, field-based insights, and SAR for the development of potent and orally bioavailable p38α MAPK inhibitors.
{"title":"Identification of structural fragments and field point-based design of novel p38α MAPK inhibitor: Integrating 2D and 3D-QSAR models with advanced in-silico techniques","authors":"Saurabh Gupta, Yogita Bansal","doi":"10.1016/j.jmgm.2025.109246","DOIUrl":"10.1016/j.jmgm.2025.109246","url":null,"abstract":"<div><div>Dysregulation of p38α MAP kinase (MAPK14) increases the production of pro-inflammatory cytokines, causing pathogenesis of inflammatory, oncological, and neurodegenerative diseases. Till date, no orally effective p38α MAPK inhibitor exists in clinics, which may be due to poor selectivity and off-target effects. This emphasizes the urgent need for the design of potential p38α MAPK inhibitors. In this study, SMILES-based 2D-QSAR and field-point-based 3D QSAR models were developed to guide the design of novel p38α MAPK inhibitors. A dataset of 207 molecules was used to developed 2D-QSAR models via Monte Carlo optimization. Among fifteen models, Split-3 of model 14 exhibited highest statistical performance and was identified as the best model. Structural fragments that either enhance or hinder activity were identified. Subsequently for 3D-QSAR approach, a pharmacophoric template was generated and employed to align dataset. This aligned dataset was utilized to developed 3D-QSAR and a 5-component model showed superior predictivity and provided SAR insights. Based on these insights, a virtual library of 14,040 compounds was designed and screened using in silico workflow such as Lipinski's Rule of Five, predicted pIC<sub>50</sub>, molecular docking, electrostatic complementarity, molecular dynamics simulations, MM/GBSA, WaterSwap, and ADMET predictions. From this virtual screening, compound P38S002073 emerged as the most promising lead candidate. Overall, this integrative approach provides important structural insights, field-based insights, and SAR for the development of potent and orally bioavailable p38α MAPK inhibitors.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109246"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145714606","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 : 2026-03-01Epub 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":"2026-03-01","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 : 2026-03-01Epub Date: 2025-12-09DOI: 10.1016/j.jmgm.2025.109251
Elena Ermakova, Yuriy Zuev
The molecular mechanisms of fish gelatin (FG)-polysaccharide interactions are crucial for designing of advanced biomaterials. While experimental studies have demonstrated that polysaccharides can enhance the FG's functional properties, the atomic-level details of these interactions remain poorly characterized. In this study, we employ molecular docking to identify preferential binding sites of gelatin and the all-atom molecular dynamics (MD) simulations to quantify the interaction energetics and complex stability, with particular focus on the role of local charge distribution along gelatin molecule. We modeled four FG fragments with varying charge distribution and analyzed their interactions with anionic and cationic polysaccharides ι-carrageenan, alginate and chitosan. The MD simulations revealed that the charge density patterns of both interacting molecules critically determine gelatin-polysaccharide binding affinity and complex stability. This work provides first 3D-structural models of FG-polysaccharide complexes, offering fundamental insight for biomaterial design.
{"title":"Charge distribution defines the mechanism of fish gelatin-polysaccharide interactions","authors":"Elena Ermakova, Yuriy Zuev","doi":"10.1016/j.jmgm.2025.109251","DOIUrl":"10.1016/j.jmgm.2025.109251","url":null,"abstract":"<div><div>The molecular mechanisms of fish gelatin (FG)-polysaccharide interactions are crucial for designing of advanced biomaterials. While experimental studies have demonstrated that polysaccharides can enhance the FG's functional properties, the atomic-level details of these interactions remain poorly characterized. In this study, we employ molecular docking to identify preferential binding sites of gelatin and the all-atom molecular dynamics (MD) simulations to quantify the interaction energetics and complex stability, with particular focus on the role of local charge distribution along gelatin molecule. We modeled four FG fragments with varying charge distribution and analyzed their interactions with anionic and cationic polysaccharides ι-carrageenan, alginate and chitosan. The MD simulations revealed that the charge density patterns of both interacting molecules critically determine gelatin-polysaccharide binding affinity and complex stability. This work provides first 3D-structural models of FG-polysaccharide complexes, offering fundamental insight for biomaterial design.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109251"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145734083","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 : 2026-03-01Epub Date: 2025-12-22DOI: 10.1016/j.jmgm.2025.109261
Yahya A. Almutawif , Saad Amin , Sajjad Ahmad , Kalsoom Khan , Asad Ullah , Abu Nasar Siddique , Faisal Ahmad
Multidrug-resistant Acinetobacter baumannii infections have driven the development of innovative therapeutic approaches to address global challenges. The present study reported that the protein belonging to the TetR family regulator AmvR from A. baumannii is bound to spermidine. Here, quantitative structure-activity relationship (QSAR) models developed from a ChEMBL dataset were used to perform an initial screening of a library of 10,860 natural chemical compounds, along with their reported minimum inhibitory concentration (MIC) scores. Machine learning models, including RF, SVM, KNN, and XGBoost, were implemented for compound classification. An RF model was selected that achieved a 96 % accuracy score on the test set. A deep learning model, CNN, was built, and a structure-based virtual screening approach was applied against A. baumannii to assess how similar these molecules are to drug likeness. In silico pharmacokinetic analysis was performed for the top candidates, including binding energy evaluation of protein-ligand docking with scores of −10.6 kcal/mol, −10.4 kcal/mol, and a control with −6 kcal/mol. Absorption, distribution, metabolism, and excretion (ADME) properties for CHEMBL-560977, CHEMBL-551116, and the control complex were also noted. Additionally, the binding mechanism was elucidated through molecular dynamics simulations over 500 ns, with binding free energy analysis (MMGBSA/PBSA) showing results of −120.55 kcal/mol, −94.99 kcal/mol, and −90.65 kcal/mol. Dynamic cross-correlation matrix (DCCM), radial distribution function (RDF), and hydrogen bonding (H-bonds) analyses were conducted, along with principal component analysis (PCA) and free energy landscape (FEL) clustering for the selected complexes. Secondary structure analysis and salt bridge assessments indicated that the newly discovered compounds are more promising than the currently available drugs. According to all docking and MD simulation results, the ligand-bound protein exhibits promising and stable behavior. Lastly, the selected compounds are recommended for further experimental studies and could serve as potent inhibitors of A. baumannii infection.
{"title":"Breaking resistance with machine and deep learning: A computational intelligence hunt for AmvR (TetR) inhibitors in Acinetobacter baumannii","authors":"Yahya A. Almutawif , Saad Amin , Sajjad Ahmad , Kalsoom Khan , Asad Ullah , Abu Nasar Siddique , Faisal Ahmad","doi":"10.1016/j.jmgm.2025.109261","DOIUrl":"10.1016/j.jmgm.2025.109261","url":null,"abstract":"<div><div>Multidrug-resistant <em>Acinetobacter baumannii</em> infections have driven the development of innovative therapeutic approaches to address global challenges. The present study reported that the protein belonging to the TetR family regulator AmvR from <em>A. baumannii</em> is bound to spermidine. Here, quantitative structure-activity relationship (QSAR) models developed from a ChEMBL dataset were used to perform an initial screening of a library of 10,860 natural chemical compounds, along with their reported minimum inhibitory concentration (MIC) scores. Machine learning models, including RF, SVM, KNN, and XGBoost, were implemented for compound classification. An RF model was selected that achieved a 96 % accuracy score on the test set. A deep learning model, CNN, was built, and a structure-based virtual screening approach was applied against <em>A. baumann</em>ii to assess how similar these molecules are to drug likeness. In silico pharmacokinetic analysis was performed for the top candidates, including binding energy evaluation of protein-ligand docking with scores of −10.6 kcal/mol, −10.4 kcal/mol, and a control with −6 kcal/mol. Absorption, distribution, metabolism, and excretion (ADME) properties for CHEMBL-560977, CHEMBL-551116, and the control complex were also noted. Additionally, the binding mechanism was elucidated through molecular dynamics simulations over 500 ns, with binding free energy analysis (MMGBSA/PBSA) showing results of −120.55 kcal/mol, −94.99 kcal/mol, and −90.65 kcal/mol. Dynamic cross-correlation matrix (DCCM), radial distribution function (RDF), and hydrogen bonding (H-bonds) analyses were conducted, along with principal component analysis (PCA) and free energy landscape (FEL) clustering for the selected complexes. Secondary structure analysis and salt bridge assessments indicated that the newly discovered compounds are more promising than the currently available drugs. According to all docking and MD simulation results, the ligand-bound protein exhibits promising and stable behavior. Lastly, the selected compounds are recommended for further experimental studies and could serve as potent inhibitors of <em>A. baumannii</em> infection.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109261"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827841","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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