Pub Date : 2025-12-02DOI: 10.1016/j.jmgm.2025.109248
R. Rajeswara Palanichamy , A. Amudhavalli , R. Meenakshi , T.M. Chithresh , M. Manikandan , K. Iyakutti , Y. Kawazoe
First-principles calculations based on the density functional theory (DFT) are employed to study the structural, electronic, magnetic, optical, and thermal properties of new Zr based half- Heusler compounds with α, β and γ phases. The most stable state is predicted as ferromagnetic α-phase. Electronic structure predicted the half metallic property and indirect band gap nature of the compounds. The magnetic moment around 1μB obeys the Slater-Pauling rule. The spin polarization at the Fermi level is 100 % which also supports the half metallic behavior. The high Curie temperature values 342.7 K, 1082.7 K and 835.3 K of these half-Heusler alloys make them strong ferromagnets. The high value of dielectric function leads to better polarization, stability and energy storage. The dielectric constant values of ZrFeAs, ZrFeSb and ZrFeBi are found to be 19.4, 18.6 and 18.1 respectively. The absence of negative frequency modes in phonon dispersion curve suggests that these alloys are dynamically stable. The zero-point energy values of ZrFeAs, ZrFeSb and ZrFeBi are 8.4 kJ/mol, 8.06 kJ/mol and 6.79 kJ/mol respectively.
{"title":"Computational investigation of high Curie temperature, magnetic anisotropy and optical properties of new Zr based half-Heusler compounds","authors":"R. Rajeswara Palanichamy , A. Amudhavalli , R. Meenakshi , T.M. Chithresh , M. Manikandan , K. Iyakutti , Y. Kawazoe","doi":"10.1016/j.jmgm.2025.109248","DOIUrl":"10.1016/j.jmgm.2025.109248","url":null,"abstract":"<div><div>First-principles calculations based on the density functional theory (DFT) are employed to study the structural, electronic, magnetic, optical, and thermal properties of new Zr based half- Heusler compounds with α, β and γ phases. The most stable state is predicted as ferromagnetic α-phase. Electronic structure predicted the half metallic property and indirect band gap nature of the compounds. The magnetic moment around 1μ<sub>B</sub> obeys the Slater-Pauling rule. The spin polarization at the Fermi level is 100 % which also supports the half metallic behavior. The high Curie temperature values 342.7 K, 1082.7 K and 835.3 K of these half-Heusler alloys make them strong ferromagnets. The high value of dielectric function leads to better polarization, stability and energy storage. The dielectric constant values of ZrFeAs, ZrFeSb and ZrFeBi are found to be 19.4, 18.6 and 18.1 respectively. The absence of negative frequency modes in phonon dispersion curve suggests that these alloys are dynamically stable. The zero-point energy values of ZrFeAs, ZrFeSb and ZrFeBi are 8.4 kJ/mol, 8.06 kJ/mol and 6.79 kJ/mol respectively.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109248"},"PeriodicalIF":3.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682694","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 : 2025-12-01Epub Date: 2025-08-05DOI: 10.1016/j.jmgm.2025.109130
Mohamed J Saadh, Faris Anad Muhammad, Rafid Jihad Albadr, Suhas Ballal, Abhayveer Singh, Anita Devi, Kamal Kant Joshi, Saida Saidkhodjaeva, Waam Mohammed Taher, Mariem Alwan, Mahmood Jasem Jawad, Ali M Ali Al-Nuaimi
The Marburg virus, a close relative of the Ebola virus, is a menacing Filovirus known for its devastating outbreaks in Germany and recent outbreaks in Guinea and Tanzania. This deadly pathogen triggers severe hemorrhagic fever, posing a grave threat to public health and demanding urgent attention from the global medical community. The amino acid sequence and PDB of the Envelope glycoprotein (GP) were extracted from RCSB for use in predicting epitopes (IEDB server). The construction of the multi-epitope vaccine included an adjuvant and linkers (AAY, EAAAK, GPGPG), which were assessed with the ProtParam tool to characterize their physico-chemical properties. Additionally, modeling was carried out with the Robetta server, and the modeled vaccine was docked with Toll-like receptor 4 (TLR4). Finally, immune and molecular dynamic simulations were implemented using the C-ImmSim and GROMACS packages. The final multi-epitope vaccine consists of 211 amino acids, created with 5 CTL and 4 HTL epitopes that were validated and passed assessments for antigenicity, allergenicity, and toxicity. The modeled multi-epitope vaccine was evaluated and demonstrated high model quality. The best molecular docking candidate was selected and evaluated using PDBsum. Subsequently, by assessing RMSD, RMSF, and Gyration, the molecular dynamic simulation revealed considerable binding with TLR4, and the complex remained stable throughout the simulation. Ultimately, the multi-epitope vaccine can stimulate both humoral and cell-mediated immune responses, validated computationally. The overall implication of this investigation shows the potency of the multi-epitope construct as an efficient protective vaccine against the Marburg virus.
{"title":"Structure-based design of a multi-epitope vaccine candidate against marburg virus using immunoinformatics and dynamics simulations.","authors":"Mohamed J Saadh, Faris Anad Muhammad, Rafid Jihad Albadr, Suhas Ballal, Abhayveer Singh, Anita Devi, Kamal Kant Joshi, Saida Saidkhodjaeva, Waam Mohammed Taher, Mariem Alwan, Mahmood Jasem Jawad, Ali M Ali Al-Nuaimi","doi":"10.1016/j.jmgm.2025.109130","DOIUrl":"10.1016/j.jmgm.2025.109130","url":null,"abstract":"<p><p>The Marburg virus, a close relative of the Ebola virus, is a menacing Filovirus known for its devastating outbreaks in Germany and recent outbreaks in Guinea and Tanzania. This deadly pathogen triggers severe hemorrhagic fever, posing a grave threat to public health and demanding urgent attention from the global medical community. The amino acid sequence and PDB of the Envelope glycoprotein (GP) were extracted from RCSB for use in predicting epitopes (IEDB server). The construction of the multi-epitope vaccine included an adjuvant and linkers (AAY, EAAAK, GPGPG), which were assessed with the ProtParam tool to characterize their physico-chemical properties. Additionally, modeling was carried out with the Robetta server, and the modeled vaccine was docked with Toll-like receptor 4 (TLR4). Finally, immune and molecular dynamic simulations were implemented using the C-ImmSim and GROMACS packages. The final multi-epitope vaccine consists of 211 amino acids, created with 5 CTL and 4 HTL epitopes that were validated and passed assessments for antigenicity, allergenicity, and toxicity. The modeled multi-epitope vaccine was evaluated and demonstrated high model quality. The best molecular docking candidate was selected and evaluated using PDBsum. Subsequently, by assessing RMSD, RMSF, and Gyration, the molecular dynamic simulation revealed considerable binding with TLR4, and the complex remained stable throughout the simulation. Ultimately, the multi-epitope vaccine can stimulate both humoral and cell-mediated immune responses, validated computationally. The overall implication of this investigation shows the potency of the multi-epitope construct as an efficient protective vaccine against the Marburg virus.</p>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"141 ","pages":"109130"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812116","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 : 2025-12-01Epub Date: 2025-08-07DOI: 10.1016/j.jmgm.2025.109137
Radhika P V, J T Anandhi, S K Amjath Kudos, R S Bemina, Binisha B, S Madhan Kumar, T Joselin Beaula
In the quest to combat rising antimicrobial resistance, this study explores the synthesis, characterization, and pharmacological potential of carbamide compounds combined with Butanedioic acid. Leveraging both experimental and computational methodologies, we synthesized Carbamide-Butanedioic Acid (CBA) crystals through a controlled evaporation process. Characterization was conducted using techniques such as FT-IR, UV-visible spectroscopy, powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). These methods elucidated the crystal structure, molecular interactions, and physicochemical properties of the synthesized compounds. Computational studies, employing Density Functional Theory (DFT) and other quantum chemical calculations, provided insights into the molecular geometry, vibrational spectra, and electronic properties, including the identification of reactive sites and intermolecular interactions. The antibacterial efficacy of the synthesized compounds was assessed using the agar well diffusion method, revealing promising inhibitory effects against bacterial pathogens. This study highlights CBA compounds as promising next-generation antibacterial agents, providing a new approach to tackle antimicrobial resistance.
{"title":"Efficient structure elucidation and investigation on the antibacterial activity of Carbamide-Butanedioic Acid: DFT perspectives.","authors":"Radhika P V, J T Anandhi, S K Amjath Kudos, R S Bemina, Binisha B, S Madhan Kumar, T Joselin Beaula","doi":"10.1016/j.jmgm.2025.109137","DOIUrl":"10.1016/j.jmgm.2025.109137","url":null,"abstract":"<p><p>In the quest to combat rising antimicrobial resistance, this study explores the synthesis, characterization, and pharmacological potential of carbamide compounds combined with Butanedioic acid. Leveraging both experimental and computational methodologies, we synthesized Carbamide-Butanedioic Acid (CBA) crystals through a controlled evaporation process. Characterization was conducted using techniques such as FT-IR, UV-visible spectroscopy, powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). These methods elucidated the crystal structure, molecular interactions, and physicochemical properties of the synthesized compounds. Computational studies, employing Density Functional Theory (DFT) and other quantum chemical calculations, provided insights into the molecular geometry, vibrational spectra, and electronic properties, including the identification of reactive sites and intermolecular interactions. The antibacterial efficacy of the synthesized compounds was assessed using the agar well diffusion method, revealing promising inhibitory effects against bacterial pathogens. This study highlights CBA compounds as promising next-generation antibacterial agents, providing a new approach to tackle antimicrobial resistance.</p>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"141 ","pages":"109137"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812115","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 : 2025-12-01DOI: 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":"2025-12-01","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 : 2025-12-01Epub Date: 2025-08-06DOI: 10.1016/j.jmgm.2025.109134
Georgy S Malakhov, Dmitry A Karasev, Boris N Sobolev
Virtual screening of biologically active compounds is widely applied for the search of drug leads. The well-known methods of structure-activity relationship (SAR) are based on the chemical structure comparison. In the last years, an approach known as proteochemometrics (PCM) has also gained popularity. PCM extends the capabilities of SAR by incorporating the protein target descriptors into the model. Unlike SAR, PCM can be used to predict new targets with unknown spectra of ligands. As both approaches can be used to predict ligands for the known proteins, several researchers apply PCM to solve this task, without providing compelling reasons to support the superiority of the PCM approach over SAR. To correctly compare the performance of SAR and PCM in the given situation, we have developed a special validation scheme. As a result, we did not find any advantages of PCM over SAR in the prediction of ligands for the protein with an established ligand spectrum. At the same time, the validation procedure commonly used for PCM models considerably inflates the evaluation scores compared to our technique. Widespread use of such validation scheme leads to conclusions that PCM has great advantage over SAR in contrast to our findings. Thus, our study emphasizes that a transparent and correct validation scheme is essential for comparison of different methods.
{"title":"Comparative efficiency of structure activity relationship and proteochemometric modelling.","authors":"Georgy S Malakhov, Dmitry A Karasev, Boris N Sobolev","doi":"10.1016/j.jmgm.2025.109134","DOIUrl":"10.1016/j.jmgm.2025.109134","url":null,"abstract":"<p><p>Virtual screening of biologically active compounds is widely applied for the search of drug leads. The well-known methods of structure-activity relationship (SAR) are based on the chemical structure comparison. In the last years, an approach known as proteochemometrics (PCM) has also gained popularity. PCM extends the capabilities of SAR by incorporating the protein target descriptors into the model. Unlike SAR, PCM can be used to predict new targets with unknown spectra of ligands. As both approaches can be used to predict ligands for the known proteins, several researchers apply PCM to solve this task, without providing compelling reasons to support the superiority of the PCM approach over SAR. To correctly compare the performance of SAR and PCM in the given situation, we have developed a special validation scheme. As a result, we did not find any advantages of PCM over SAR in the prediction of ligands for the protein with an established ligand spectrum. At the same time, the validation procedure commonly used for PCM models considerably inflates the evaluation scores compared to our technique. Widespread use of such validation scheme leads to conclusions that PCM has great advantage over SAR in contrast to our findings. Thus, our study emphasizes that a transparent and correct validation scheme is essential for comparison of different methods.</p>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"141 ","pages":"109134"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812114","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 : 2025-11-29DOI: 10.1016/j.jmgm.2025.109245
Zekeriya Duzgun , Zuhal Eroglu
Traditional protein-protein docking algorithms face significant limitations when handling flexible protein systems, particularly where conformational flexibility plays crucial roles in binding specificity. This study developed and validated a Coarse-Grained Cubic Orientation Approach (CG-COA) that systematically samples six cubic orientations combined with coarse-grained molecular dynamics simulations and MM/PBSA free energy calculations. As a local docking approach, CG-COA requires prior knowledge of putative bioactive surfaces and focuses computational resources on biologically relevant binding orientations.
The methodology was validated using six protein complexes: four core systems (PDB codes: 2HD5, 1MIM, 3QML, 2MWS) representing diverse binding mechanisms, plus two extreme scenarios (2MZD: intrinsically disordered proteins; 2QCS-1RGS: large conformational changes). Benchmark comparisons against established docking methods (ZDOCK and ClusPro) evaluated relative performance across different system types.
Results demonstrated robust performance with overall AUROC of 0.94, achieving F-scores up to 1.00 for well-defined systems. Benchmark analysis revealed system-dependent performance: significant advantages for flexible systems (3QML: 3.7–5.1-fold improvement over rigid-body methods) but inferior performance for rigid interfaces (2HD5: outperformed by conventional approaches). Extreme docking scenarios revealed clear method limitations with poor structural accuracy (RMSDs >13 Å), defining important applicability boundaries. The approach correctly diagnosed inherently flexible systems (2MWS) by not converging to single conformations.
CG-COA addresses specific limitations of conventional protein-protein docking methods for systems with moderate conformational flexibility while clearly defining applicability boundaries. The methodology is unsuitable for extensive structural rearrangements or intrinsically disordered regions. The dual capability to identify native binding modes and diagnose flexibility provides valuable guidance for protein interaction studies.
{"title":"CG-COA: a coarse-grained cubic orientation approach for systematic protein-protein docking validation","authors":"Zekeriya Duzgun , Zuhal Eroglu","doi":"10.1016/j.jmgm.2025.109245","DOIUrl":"10.1016/j.jmgm.2025.109245","url":null,"abstract":"<div><div>Traditional protein-protein docking algorithms face significant limitations when handling flexible protein systems, particularly where conformational flexibility plays crucial roles in binding specificity. This study developed and validated a Coarse-Grained Cubic Orientation Approach (CG-COA) that systematically samples six cubic orientations combined with coarse-grained molecular dynamics simulations and MM/PBSA free energy calculations. As a local docking approach, CG-COA requires prior knowledge of putative bioactive surfaces and focuses computational resources on biologically relevant binding orientations.</div><div>The methodology was validated using six protein complexes: four core systems (PDB codes: <span><span>2HD5</span><svg><path></path></svg></span>, <span><span>1MIM</span><svg><path></path></svg></span>, <span><span>3QML</span><svg><path></path></svg></span>, <span><span>2MWS</span><svg><path></path></svg></span>) representing diverse binding mechanisms, plus two extreme scenarios (2MZD: intrinsically disordered proteins; 2QCS-1RGS: large conformational changes). Benchmark comparisons against established docking methods (ZDOCK and ClusPro) evaluated relative performance across different system types.</div><div>Results demonstrated robust performance with overall AUROC of 0.94, achieving F-scores up to 1.00 for well-defined systems. Benchmark analysis revealed system-dependent performance: significant advantages for flexible systems (3QML: 3.7–5.1-fold improvement over rigid-body methods) but inferior performance for rigid interfaces (2HD5: outperformed by conventional approaches). Extreme docking scenarios revealed clear method limitations with poor structural accuracy (RMSDs >13 Å), defining important applicability boundaries. The approach correctly diagnosed inherently flexible systems (2MWS) by not converging to single conformations.</div><div>CG-COA addresses specific limitations of conventional protein-protein docking methods for systems with moderate conformational flexibility while clearly defining applicability boundaries. The methodology is unsuitable for extensive structural rearrangements or intrinsically disordered regions. The dual capability to identify native binding modes and diagnose flexibility provides valuable guidance for protein interaction studies.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109245"},"PeriodicalIF":3.0,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654704","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 : 2025-11-29DOI: 10.1016/j.jmgm.2025.109244
Gonzalo A. Olivera-Gonzales , Alicia Arica-Sosa , Leonardo J. Monroy-Cruz , Cintia A. Menéndez , Miguel Quiliano
Tuberculosis (TB) is one of the leading causes of mortality worldwide. Although it is considered a curable disease, the emergence of strains resistant to conventional treatments has rendered it a significant public health problem. Therefore, it is necessary to identify new therapeutic targets to combat this disease. The serine/threonine protein kinase A (PknA) has gained relevance due to its essential role in cell wall synthesis and the growth of Mycobacterium tuberculosis (Mtb). In the present study, an integrative molecular modeling approach was developed for the screening of libraries containing 1 581 625 compounds to identify potential PknA inhibitors. Pharmacophore-based virtual screening, followed by molecular docking, steered molecular dynamics, and binding free energy calculations have identified compound CHEMBL552033 as a promising hit compound. In addition, in silico ADME profiling, pharmacophore-based toxicity assessment, and kinase selectivity screening were performed to evaluate overall suitability as a promising hit. Molecular dynamics simulations of the PknA–CHEMBL552033 complex demonstrated the stability of the interaction, and the binding free energy values obtained by MM-GBSA (−49.54 ± 7.08 kcal/mol) and LIE-D method (−7.01 ± 1.26 kcal/mol) emphasize the potential of CHEMBL552033 as a potential inhibitor for the development of novel anti-TB therapies.
{"title":"Identification of potential inhibitors of Mycobacterium tuberculosis PknA using integrative molecular modeling approaches","authors":"Gonzalo A. Olivera-Gonzales , Alicia Arica-Sosa , Leonardo J. Monroy-Cruz , Cintia A. Menéndez , Miguel Quiliano","doi":"10.1016/j.jmgm.2025.109244","DOIUrl":"10.1016/j.jmgm.2025.109244","url":null,"abstract":"<div><div>Tuberculosis (TB) is one of the leading causes of mortality worldwide. Although it is considered a curable disease, the emergence of strains resistant to conventional treatments has rendered it a significant public health problem. Therefore, it is necessary to identify new therapeutic targets to combat this disease. The serine/threonine protein kinase A (PknA) has gained relevance due to its essential role in cell wall synthesis and the growth of <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>). In the present study, an integrative molecular modeling approach was developed for the screening of libraries containing 1 581 625 compounds to identify potential PknA inhibitors. Pharmacophore-based virtual screening, followed by molecular docking, steered molecular dynamics, and binding free energy calculations have identified compound CHEMBL552033 as a promising hit compound. In addition, <em>in silico</em> ADME profiling, pharmacophore-based toxicity assessment, and kinase selectivity screening were performed to evaluate overall suitability as a promising hit. Molecular dynamics simulations of the PknA–CHEMBL552033 complex demonstrated the stability of the interaction, and the binding free energy values obtained by MM-GBSA (−49.54 ± 7.08 kcal/mol) and LIE-D method (−7.01 ± 1.26 kcal/mol) emphasize the potential of CHEMBL552033 as a potential inhibitor for the development of novel anti-TB therapies.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109244"},"PeriodicalIF":3.0,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682778","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 : 2025-11-27DOI: 10.1016/j.jmgm.2025.109236
Ricardo Pino-Rios , Carolina Olea-Ulloa
In this work, we explore the pH-responsive stability of the supramolecular host–guest complex formed by the tetracationic cyclophane ExBox4+ and diphenylporphyrin. This study builds upon the supramolecular concept originally introduced for ExBox4+–porphyrin systems by Stoddart and co-workers [1], providing a theoretical perspective on their pH-dependent behavior. We study how porphyrin protonation modulates geometry, binding interactions, and supramolecular behavior using a methodology that integrates density functional theory (DFT), energy decomposition analysis (EDA), non-covalent interaction (NCI) analysis, and molecular dynamics (MD) simulations. Our findings reveal that π–π stacking and electrostatic forces stabilize the neutral complex, whereas protonation breaks host–guest complementarity, weakening the assembly and allowing partial guest release. This set of methodologies provides a predictive tool for recognizing supramolecular assemblies, highlighting the potential of ExBox4+ as a pH-sensitive sequestering agent and showing how a combined DFT, EDA, NCI, and MD framework can serve as a practical approach to investigate controlled release processes in supramolecular systems.
{"title":"Exploring the stability and pH-responsive behavior of the diphenylporphyrin@ExBOX4+ complex for controlled drug release: A theoretical study","authors":"Ricardo Pino-Rios , Carolina Olea-Ulloa","doi":"10.1016/j.jmgm.2025.109236","DOIUrl":"10.1016/j.jmgm.2025.109236","url":null,"abstract":"<div><div>In this work, we explore the pH-responsive stability of the supramolecular host–guest complex formed by the tetracationic cyclophane ExBox<sup>4+</sup> and diphenylporphyrin. This study builds upon the supramolecular concept originally introduced for ExBox<sup>4+</sup>–porphyrin systems by Stoddart and co-workers [1], providing a theoretical perspective on their pH-dependent behavior. We study how porphyrin protonation modulates geometry, binding interactions, and supramolecular behavior using a methodology that integrates density functional theory (DFT), energy decomposition analysis (EDA), non-covalent interaction (NCI) analysis, and molecular dynamics (MD) simulations. Our findings reveal that π–π stacking and electrostatic forces stabilize the neutral complex, whereas protonation breaks host–guest complementarity, weakening the assembly and allowing partial guest release. This set of methodologies provides a predictive tool for recognizing supramolecular assemblies, highlighting the potential of ExBox<sup>4+</sup> as a pH-sensitive sequestering agent and showing how a combined DFT, EDA, NCI, and MD framework can serve as a practical approach to investigate controlled release processes in supramolecular systems.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109236"},"PeriodicalIF":3.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617524","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 : 2025-11-27DOI: 10.1016/j.jmgm.2025.109234
Qinghua Yang , Maodong Guo , Xiao Zhu
Ursolic acid (UA) exhibits anti-inflammatory and anti-tumor properties. Developing a nanodrug delivery system for UA can improve its bioavailability. Transition metal sulfides, owing to their distinctive physicochemical characteristics, have emerged as the predominant two-dimensional nanostructures utilized in the advancement of nanodrug delivery systems in recent years. This study employs first-principles calculations to assess the viability of monolayer PtS2 as a carrier for UA. The results indicate that monolayer PtS2 exhibits structural stability as a UA carrier, with an adsorption energy of −3.84 eV. Mulliken charge analysis reveals that UA donates 0.34 |e| to PtS2. Additionally, the application of strain induces a redshift in the optical absorption peak of monolayer PtS2, thereby enhancing its optical absorption capabilities. Furthermore, monolayer PtS2 displays favorable temperature-controlled release properties when utilized as a delivery vehicle for Ursolic acid. These results offer theoretical insights that could inform the development of innovative drug carriers and significantly contribute to the treatment of inflammatory bowel disease.
{"title":"Theoretical calculations of monolayer PtS2 as a drug delivery carrier for ursolic acid","authors":"Qinghua Yang , Maodong Guo , Xiao Zhu","doi":"10.1016/j.jmgm.2025.109234","DOIUrl":"10.1016/j.jmgm.2025.109234","url":null,"abstract":"<div><div>Ursolic acid (UA) exhibits anti-inflammatory and anti-tumor properties. Developing a nanodrug delivery system for UA can improve its bioavailability. Transition metal sulfides, owing to their distinctive physicochemical characteristics, have emerged as the predominant two-dimensional nanostructures utilized in the advancement of nanodrug delivery systems in recent years. This study employs first-principles calculations to assess the viability of monolayer PtS<sub>2</sub> as a carrier for UA. The results indicate that monolayer PtS<sub>2</sub> exhibits structural stability as a UA carrier, with an adsorption energy of −3.84 eV. Mulliken charge analysis reveals that UA donates 0.34 |e| to PtS<sub>2</sub>. Additionally, the application of strain induces a redshift in the optical absorption peak of monolayer PtS<sub>2</sub>, thereby enhancing its optical absorption capabilities. Furthermore, monolayer PtS<sub>2</sub> displays favorable temperature-controlled release properties when utilized as a delivery vehicle for Ursolic acid. These results offer theoretical insights that could inform the development of innovative drug carriers and significantly contribute to the treatment of inflammatory bowel disease.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109234"},"PeriodicalIF":3.0,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617525","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 : 2025-11-25DOI: 10.1016/j.jmgm.2025.109233
Sattar Arshadi , Mina Salary , Omid Marvi
This study employs density functional theory (DFT) with Grimme's D3-BJ dispersion correction to investigate the adsorption of six hazardous industrial gases (HIGas) including cyanogen chloride (CNCl), formaldehyde (CH2O), cyanogen (C2N2), hydrogen cyanide (HCN), dichloroacetylene (C2Cl2), and phosgene (COCl2) on a magnesium-porphyrin nanoring sensor (NR4P4Mg4). The interactions are characterized as physical and reversible, with BSSE corrected adsorption energies ranging from −1.90 to −18.36 kcal/mol. Gas adsorption induces a significant band gap increase of approximately 122 %, substantially reducing electrical conductivity, while maintaining adsorption distances of 2.16–3.09 Å consistent with physisorption. The calculated recovery times spanning picoseconds to microseconds indicate rapid adsorption-desorption cycles. Electronic structure analysis through Natural Bond Orbital (NBO) and Frontier Molecular Orbital (FMO) calculations reveals consistent electron transfer from gas molecule HOMOs to the nanoring's LUMO. The presence of four distinct adsorption sites enables saturation-free detection of HIGas, with demonstrated resilience against atmospheric interference from nitrogen and humidity.
{"title":"First-principles design of a Mg-porphyrin nanoring sensor via dipole moment and dispersion energy engineering for high-sensitivity detection of hazardous industrial gases","authors":"Sattar Arshadi , Mina Salary , Omid Marvi","doi":"10.1016/j.jmgm.2025.109233","DOIUrl":"10.1016/j.jmgm.2025.109233","url":null,"abstract":"<div><div>This study employs density functional theory (DFT) with Grimme's D3-BJ dispersion correction to investigate the adsorption of six hazardous industrial gases (HI<sub>Gas</sub>) including cyanogen chloride (CNCl), formaldehyde (CH<sub>2</sub>O), cyanogen (C<sub>2</sub>N<sub>2</sub>), hydrogen cyanide (HCN), dichloroacetylene (C<sub>2</sub>Cl<sub>2</sub>), and phosgene (COCl<sub>2</sub>) on a magnesium-porphyrin nanoring sensor (NR<sub>4</sub>P<sub>4</sub>Mg<sub>4</sub>). The interactions are characterized as physical and reversible, with BSSE corrected adsorption energies ranging from −1.90 to −18.36 kcal/mol. Gas adsorption induces a significant band gap increase of approximately 122 %, substantially reducing electrical conductivity, while maintaining adsorption distances of 2.16–3.09 Å consistent with physisorption. The calculated recovery times spanning picoseconds to microseconds indicate rapid adsorption-desorption cycles. Electronic structure analysis through Natural Bond Orbital (NBO) and Frontier Molecular Orbital (FMO) calculations reveals consistent electron transfer from gas molecule HOMOs to the nanoring's LUMO. The presence of four distinct adsorption sites enables saturation-free detection of HI<sub>Gas</sub>, with demonstrated resilience against atmospheric interference from nitrogen and humidity.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"143 ","pages":"Article 109233"},"PeriodicalIF":3.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145610622","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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