Frontiers in Chemistry最新文献

{"title":"Engineering a hemoglobin variant with enhanced stability and oxygen affinity using a protein language model.","authors":"Sergey Shityakov, Alexander S Novikov, Ekaterina V Skorb, Thomas Dandekar","doi":"10.3389/fchem.2026.1898272","DOIUrl":"10.3389/fchem.2026.1898272","url":null,"abstract":"<p><strong>Introduction: </strong>Engineered hemoglobin variants offer therapeutic promise for artificial blood substitutes and oxygen therapeutics, but rational design is constrained by protein stability and heme-binding. Protein language models (pLMs) predict mutation fitness, yet their integration with biophysical validation remains limited.</p><p><strong>Methods: </strong>We developed a hybrid pipeline combining pLM (ESM3) with molecular docking, Monte Carlo simulation, molecular dynamics, MM-GBSA/PBSA binding free energy calculations, and density functional theory (DFT) to engineer a stabilized hemoglobin variant (esmHb) with enhanced oxygen affinity, benchmarking against the clinically characterized Hb Fort de France mutation (α45 His→Arg).</p><p><strong>Results: </strong>ESM3 accurately assessed the fitness effect of the Hb Fort de France mutation and generated structurally stable esmHb models. Compared with the wild-type variant (wtHb), esmHb exhibited improved thermodynamic stability (ΔG: -18.48 vs. -12.22 kcal/mol), increased heme-binding affinity (ΔGbind: -11.79 vs. -8.42 kcal/mol), and greater thermodynamic favorability of oxidation according to DFT calculations (ΔE: -173.1 vs. -149.9 kcal/mol). MM-GBSA and MM-PBSA binding free energy calculations further supported improved protein-heme and protein-protein interactions, with esmHb showing more favorable values in both implicit solvation models. Statistical significance (p < 0.05) was reached for protein-protein interactions via both methods and for protein-heme interactions via MM-PBSA. We interpret the MM-GBSA results as a suggestive trend rather than definitive evidence.</p><p><strong>Discussion: </strong>This work establishes a generalizable framework for pLM-driven protein engineering applicable to therapeutic Hb variants and beyond.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"14 ","pages":"1898272"},"PeriodicalIF":5.3,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adsorption-dominated interfacial regulation by sarcosine via hydrogen-bond water modulation for stable Zn metal anodes.","authors":"Zijing Wang, Haolin Ju, Hao Zhang, Yiqian Yang, Huan Liu, Bin Cao, Jie Ding, Bin Xu","doi":"10.3389/fchem.2026.1986660","DOIUrl":"10.3389/fchem.2026.1986660","url":null,"abstract":"<p><p>Aqueous zinc-ion batteries (AZIBs) hold great promise for safe and low-cost energy storage, yet their practical application is seriously hindered by the hydrogen evolution reaction (HER), uncontrolled dendrite growth, and inert byproduct (Zn4SO4(OH)6·xH2O) deposition on the Zn anode. In this work, sarcosine (Sar) was adopted as a multifunctional bipolar electrolyte additive, and first-principles calculations combined with electrochemical tests and interfacial characterizations were performed to reveal its adsorption-dominated interfacial stabilization mechanism. Sar strongly adsorbs on the Zn surface to homogenize Zn2+ flux, regulate the electric field distribution, and reconfigure the interfacial environment. Meanwhile, Sar forms strong intermolecular hydrogen bonds with water molecules via its amino and carboxyl groups, reducing free water activity and suppressing HER. First-principles calculations verify the favorable adsorption configuration and high adsorption energy of Sar on the Zn surface. As a result, the Zn||Zn symmetric cell delivers ultra-long cycling stability over 2100 h at 1 mA cm-2, and the Zn||Cu half-cell exhibits a high average Coulombic efficiency of 99.7%. The full cell with ZnI@CNT-AC cathode maintains excellent capacity retention after 3000 cycles. This work provides a simple, green, and low-cost strategy for stabilizing Zn anodes toward practical aqueous zinc-ion batteries.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"14 ","pages":"1986660"},"PeriodicalIF":5.3,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Quinoline and <i>N</i>-heterocycle analogues as lead structures for the development of antiprotozoal agents.","authors":"Angel H Romero, Gustavo Benaim, Jaime Charris, Hugo Cerecetto","doi":"10.3389/fchem.2026.2005043","DOIUrl":"10.3389/fchem.2026.2005043","url":null,"abstract":"","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"14 ","pages":"2005043"},"PeriodicalIF":5.3,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel digital identification strategy for licorice raw materials: TCM-ID with common/exclusive ion matrices and hierarchical matching.","authors":"Xianrui Wang, Yu Wu, Lizhi Wan, Jiating Zhang, Fangliang He, Wenguang Jing, Jia Chen, Xianlong Cheng, Yongqiang Lin","doi":"10.3389/fchem.2026.1918761","DOIUrl":"10.3389/fchem.2026.1918761","url":null,"abstract":"<p><strong>Introduction: </strong><i>Glycyrrhiza uralensis</i> Fisch. (GUF) and <i>Glycyrrhiza inflata</i> Bat. (GIB) are two official botanical origins of Glycyrrhizae Radix et Rhizoma (GRR). Accurate identification of botanical origin is critical for ensuring efficacy stability and clinical medication safety.</p><p><strong>Methods: </strong>In this study, an innovative method integrating liquid chromatography-mass spectrometry (LC-MS) with the TCM digital identity (TCM-ID) concept was established for rapid and precise origin authentication of GUF and GIB. Common ion matrix (CIM) and exclusive ion matrix (EIM) of GUF and GIB were systematically constructed to calculate matching confidence (MC) and confidence increment rate (CIR), and a hierarchical matching strategy (HMS) was developed to improve identification accuracy. Meanwhile, the chemometric analysis was adopted to screen differential chemical markers.</p><p><strong>Results: </strong>The results demonstrated that GUF and GIB could be rapidly and specifically distinguished with thresholds of MC ≥ 70% and CIR ≥ 6.00. Compared to CIM, the EIM exhibited better species specificity, and chemometric analysis identified seven differential markers: Licoricidin, Licoricone, and Glycycoumarin for GUF, and Licochalcone A, Licochalcone B, Echinatin, and Glabrol for GIB.</p><p><strong>Discussion: </strong>This study provides a novel and feasible approach for botanical origin identification of GUF and GIB, demonstrating that the TCM-ID strategy is a promising method for origin traceability and quality evaluation of GUF and GIB.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"14 ","pages":"1918761"},"PeriodicalIF":5.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13668877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of novel Copper(II)-hydrazone complexes for targeting the inhibition of human osteosarcoma growth.","authors":"Lucía Santa Maria de la Parra, Olivia Espindola-Moreno, Matías H Assandri, Gustavo A Echeverría, Oscar E Piro, Gonzalo Scalese, Ignacio E León","doi":"10.3389/fchem.2026.1897476","DOIUrl":"10.3389/fchem.2026.1897476","url":null,"abstract":"<p><strong>Introduction: </strong>Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults and remains associated with poor clinical outcomes due to recurrence, metastasis, and resistance to conventional chemotherapy. In recent years, copper-based compounds have emerged as promising anticancer agents because of their unique redox properties and ability to target multiple cellular pathways.</p><p><strong>Methods: </strong>In this work, we synthesized and characterized two hydrazone ligands, (<i>E</i>)-<i>N</i>'-(2-hydroxybenzylidene)furan-2-carbohydrazide (L1) and (<i>E</i>)-<i>N</i>'-(2-hydroxybenzylidene)-4-methoxybenzohydrazide (L2), together with their corresponding Cu(II) complexes, CuL1 and Cu₂L2₂. The compounds were characterized by elemental analysis, spectroscopic techniques, high-resolution mass spectrometry, and single-crystal X-ray diffraction. The biological activity of the complexes was evaluated in human MG-63 osteosarcoma cells using the MTT assay. Reactive oxygen species (ROS) generation was assessed using dihydrorhodamine 123 (DHR123) after 24 h of treatment to gain insight into their mechanism of action. Their activity was further evaluated in 3D MG-63 osteosarcoma spheroids using a resazurin-based viability assay, while anti-migratory effects were assessed using the spheroid spreading assay.</p><p><strong>Results: </strong>Biological evaluation demonstrated that coordination to Cu(II) converted the inactive hydrazone ligands into highly potent anticancer agents. Both Cu(II) complexes exhibited potent cytotoxic activity in 2D cell cultures, with IC₅₀ values in the low micromolar range and significantly higher activity than cisplatin, whereas the free ligands showed no significant antiproliferative effect. Furthermore, treatment with CuL1 and Cu₂L2₂ induced a rapid increase in intracellular ROS, suggesting that oxidative stress contributes to their mechanism of action. The antitumor potential of the complexes was further assessed using multicellular tumor spheroids, where both compounds reduced spheroid viability, altered spheroid morphology, and significantly inhibited spheroid-derived cell migration.</p><p><strong>Discussion: </strong>Among the compounds studied, the binuclear complex Cu₂L2₂ displayed the highest antiproliferative activity in both 2D and 3D models. Overall, our findings demonstrate that coordination of hydrazone ligands to Cu(II) markedly enhances their biological activity and identify CuL1 and particularly the binuclear complex Cu₂L2₂ as promising candidates for the development of new copper-based therapeutics against osteosarcoma.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"14 ","pages":"1897476"},"PeriodicalIF":5.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aurophilicity as a structure-directing principle in hyperchlorinated Au_nCl_n+5 ^- (2 ≤ n ≤ 7) clusters.","authors":"Yuqing Chen, Shiyin Xu, Shuo Wang, Shuqi Li, Filip Veljković, Suzana Veličković, Xianglei Kong","doi":"10.3389/fchem.2026.1986508","DOIUrl":"10.3389/fchem.2026.1986508","url":null,"abstract":"<p><p>This study addresses the gap concerning the structural landscape of experimentally observed high-chloride Au_nCl_n+5 ^- cluster anions, whose stable geometries, aurophilic interaction patterns, thermodynamic stability, and growth pathways remain largely unexplored compared to well-characterized low- and medium-chloride analogues. To resolve this, we systematically investigate Au_nCl_n+5 ^- (n = 2-7) using laser desorption/ionization mass spectrometry (LDI-MS) and density functional theory at the TPSSh/aug-cc-pVTZ/ECP60MDF level. The results show that elevated laser intensity preferentially stabilizes these chlorine-rich clusters. Except for the smallest cluster (Au₂Cl₇ ^-), the global minima adopt nearly planar zigzag geometries, where terminal gold atoms are in a tetracoordinate Au(III) state and internal gold atoms are in an Au(I) state. Bond-length analysis reveals that only non-terminal Au-Au distances are significantly shorter than the van der Waals sum, indicating aurophilic attraction, while terminal distances show no such interaction. Aurophilicity emerges at Au₄Cl₉ ^- and rapidly stabilizes for larger clusters. Natural bond orbital (NBO) and electron localization function (ELF) analyses attribute this interaction to 6s/5d orbital delocalization between adjacent Au(I) centers, with no contribution from Au(III)-Au(I) pairs. Comparison with lower-chloride series (Au_nCl_n+1 ^- and Au_nCl_n+3 ^-) indicates that the core thermodynamic trend remains unchanged, although higher laser fluence favors chlorine-rich species via thermodynamically favored addition of two Cl atoms. This study highlights the structure-directing role of aurophilicity in hyperchlorinated gold clusters and provides a comprehensive understanding of their size-dependent structural evolution.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"14 ","pages":"1986508"},"PeriodicalIF":5.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging NPR-B agonists for cartilage and bone: from CNP biology to translational compound design.","authors":"Yasuhiko Ago, Amali Karunathilaka, Jacky M Guerrero-Vargas, Shunji Tomatsu","doi":"10.3389/fchem.2026.1949456","DOIUrl":"10.3389/fchem.2026.1949456","url":null,"abstract":"<p><p>Disorders affecting cartilage and bone development frequently originate from disrupted endochondral ossification within growth-plate cartilage. Nonetheless, few therapeutic interventions directly target the local signaling pathways governing this process. This review explores the C-type natriuretic peptide (CNP)/natriuretic peptide receptor B (NPR-B) axis as a mechanism-based therapeutic approach addressing issues in cartilage and bone, including skeletal dysplasias, genetic short-stature conditions, and acquired ailments such as bone fractures. It summarizes the production and processing of CNP <i>in vivo</i>, elucidates how NPR-B activation induces cyclic guanosine monophosphate signaling in chondrocytes, and discusses how this pathway functionally antagonizes FGFR3-driven MAPK signaling in achondroplasia. Additionally, it traces the progression from native, rapidly cleared CNP peptides to engineered agonists optimized for enhanced stability, prolonged systemic exposure, or tissue retention, emphasizing exposure design. Clinically approved agents, such as vosoritide and navepegritide, exemplify how NPR-B agonism has become a viable treatment strategy for pediatric achondroplasia. Both U.S. approvals were accelerated, with final-height confirmation required. Emerging long-acting analogs, sustained-release prodrugs, matrix-binding constructs, Fc-fusion proteins, and elastin-like polypeptide fusion platforms demonstrate the potential for molecular design adaptations to meet various therapeutic objectives. The scope of potential applications now extends to hypochondroplasia, several non-achondroplasia genetic short-stature disorders, acquired growth-plate impairments, fracture healing, and osteoarthritis-related cartilage strategies. Overall, NPR-B agonism signifies a transition from systemic endocrine-driven growth promotion to the controlled modulation of skeletal growth and repair. Future developments will necessitate long-term evidence concerning final height, skeletal proportions, functional outcomes, joint health, quality of life, and safety.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"14 ","pages":"1949456"},"PeriodicalIF":5.3,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13663181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149192640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of alkyd-based copper sorbate coatings for anti-corrosion and anti-biofouling applications.","authors":"Manikandan Thiyagarajan, Subramania Angaiah, Chao Yan, Parthipan Punniyakotti","doi":"10.3389/fchem.2026.1838832","DOIUrl":"10.3389/fchem.2026.1838832","url":null,"abstract":"<p><strong>Introduction: </strong>Biofouling is a serious problem in various industrial sectors such as shipping infrastructure, cooling water systems, and aquaculture. Biofilm formation by different types of microorganisms plays a very crucial role in this biofouling process. Biofouling on metallic surfaces accelerates aggressive corrosion processes. Therefore, it is essential to develop antifouling coatings with corrosion resistance for effective protection.</p><p><strong>Methods: </strong>In the present study, copper sorbate (CS) and copper oxide (CuO) were synthesized as antifouling pigments and characterized using a UV-vis spectrometer, Fourier transform infrared spectroscopy, X-ray diffraction, and field emission scanning electron microscopy. Both pigments in different ratios were used for the formulation of antifouling and anti-corrosion paints. Salt spray test and anti-corrosion test were performed in the presence of 3.5% NaCl solution for 30 days. Electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization were recorded for all the tested specimens.</p><p><strong>Results and discussion: </strong>The results indicate that CS-rich coatings (15%20% of CS) display higher corrosion resistance than CuO-rich coatings. The antifouling potential of the coated mild steel was evaluated by immersing them in the marine estuarine water, and surface changes were monitored at regular intervals. All coatings exhibited considerable antifouling effects up to 60 days of immersion. Notably, the CS-II coating, containing only 5% CuO with 15% of CS, showed significant fouling resistance up to 90 days. At the end of 120 days, SEM analysis confirmed that a huge number of marine microorganisms (mostly diatoms) settled on CS-I, CS-III, CS-IV, and CS-V, but minimal microorganisms were only noticed on CS-II. This could be due to the antimicrobial activity and controlled leaching behavior of both pigments in marine conditions.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"14 ","pages":"1838832"},"PeriodicalIF":5.3,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico investigation of BC₅₉ nanocage for furan adsorption and single-use detection potential.","authors":"Bader Huwaimel, Saad Alqarni, Ali Alghubayshi, Talal Alotaibi, Hashem O Alsaab, Rami M Alzhrani, Amr S Abouzied","doi":"10.3389/fchem.2026.1913300","DOIUrl":"10.3389/fchem.2026.1913300","url":null,"abstract":"<p><p>Furan is a hazardous environmental and food-processing contaminant for which rapid and accessible detection methods are needed. In this theoretical density functional theory study, pristine C₆₀ and its B- and N-substituted derivatives, BC₅₉ and NC₅₉, were evaluated as candidate materials for furan adsorption and sensing-related applications using the B97D and ωB97X-D functionals. The two functionals produced consistent qualitative rankings for the calculated properties, with Pearson correlation coefficients greater than 0.97 and Spearman coefficients of 1.00. Among the investigated systems, BC₅₉ exhibited the strongest calculated adsorption, with adsorption energies ranging from -34.61 to -49.44 kcal.mol^-1, together with the largest adsorption-induced conductivity change and a pronounced reduction in the HOMO-LUMO energy gap. NBO analysis indicated stronger donor-acceptor stabilization in BC₅₉@Furan, with E⁽²⁾ values of up to 61.81 kcal.mol^-1. QTAIM, NCI, RDG, ELF, and LOL analyses also suggested a stronger and more localized interaction at the BC₅₉@furan interface than in the C₆₀@Furan and NC₅₉@Furan complexes. However, the exceptionally long predicted desorption times indicate that BC₅₉ would not be suitable for rapidly reusable sensing applications at room temperature. Instead, it may be considered a candidate permanent adsorbent or a theoretically proposed single-use detection platform. These computational predictions represent a pre-synthesis screening step and require experimental validation before practical application.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"14 ","pages":"1913300"},"PeriodicalIF":5.3,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human β defensin type 2 based novel antimicrobial peptide prediction using both molecular dynamics simulation and artificial intelligence methods.","authors":"Ishrat Jahan, Hailemicael Lulseged Yimer, Kushal Badal, Michaela Brady, Jason J Guo, Bryce Richardson, Letu Qingge, Liqun Zhang","doi":"10.3389/fchem.2026.1913090","DOIUrl":"10.3389/fchem.2026.1913090","url":null,"abstract":"<p><p>The global health crisis triggered by SARS-CoV-2 has highlighted the urgent need for effective treatments. Although several anti-viral drugs targeting SARS-CoV-2 have been developed, there remains considerable interest in exploring natural antimicrobial peptides (AMPs) secreted by the human innate immune system as alternative therapeutic agents. Human β defensin type 2 (hBD-2) has been found to bind to the receptor-binding domain (RBD) of SARS-CoV-2 and block the virus entry. In order to design effective anti-virial drugs based on hBD-2, 32 block-mutants (mutation at more than one site simultaneously) were designed, and their interaction with RBD were predicted in terms of structural stability and binding energy. In combination with data from a total of 247 hBD-2 point-mutants reported in our previous work, artificial intelligence (AI) models were trained to design more efficient hBD-2 variants. With that, advanced AI approaches, including convolutional neural network (CNN) and long short-term memory (LSTM) models were employed to predict hBD-2 mutant sequences with potentially enhanced binding affinity with RBD compared with the wildtype peptide. Based on the predicted sequences, the AlphaFold program was applied to predict the structures of AMPs, and then all-atom molecular dynamics (MD) simulations were performed to calculate the binding interaction energies between each hBD-2-based AMP and the RBD as a measure of binding affinity. Structural stability was also evaluated through analyses of Root Mean Square Deviation (RMSD), Root Mean Squared Fluctuation (RMSF), the number of hydrogen bonds formed, and buried surface area. The results indicate that several AMPs exhibited more stable binding with RBD than the wildtype, highlighting their potential as novel hBD-2-derived antiviral candidates against SARS-CoV-2. Furthermore, based on the obtained results, the LSTM model demonstrated greater effectiveness than the CNN model in designing novel hBD-2-based anti-virial drugs against CoV-2.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"14 ","pages":"1913090"},"PeriodicalIF":5.3,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}