Journal of molecular graphics & modelling最新文献

{"title":"Unveiling the therapeutic potential of artopetelin flavonoids through computational approaches as peroxisome proliferator-activated receptor-delta (PPARδ) agonists","authors":"Ram Lal Swagat Shrestha ,&nbsp;Ashika Tamang ,&nbsp;Manila Poudel ,&nbsp;M.C. Shiva ,&nbsp;Nirmal Parajuli ,&nbsp;Aakar Shrestha ,&nbsp;Timila Shrestha ,&nbsp;Samjhana Bharati ,&nbsp;Binita Maharjan ,&nbsp;Bishnu P. Marasini ,&nbsp;Jhashanath Adhikari Subin","doi":"10.1016/j.jmgm.2025.109105","DOIUrl":"10.1016/j.jmgm.2025.109105","url":null,"abstract":"<div><div>Diabetes mellitus is a growing global health concern, with peroxisome proliferator-activated receptor-delta (PPARδ) emerging as a promising therapeutic target due to its role in glucose regulation. Flavonoids, a class of plant-derived bioactive compounds, are known for their anti-diabetic properties. The present study aims to explore the potential of artopetelin flavonoids as PPARδ activators using a range of computational approaches. Molecular docking (MD) calculations identified six artopetelin ligands with binding affinities surpassing those of the native ligand (−10.4 kcal/mol) and the reference drugs such as elafibranor (−10.0 kcal/mol) and seladelpar (−9.8 kcal/mol). The highest binding affinity was obtained for artopetelin A, with a value of −11.8 kcal/mol. All candidates, except artopetelin B, were bound at the receptor's catalytic site, suggesting potential for competitive activation. Molecular dynamics simulations (MDS) of the top five complexes revealed structural stability, with consistent root mean square deviation (RMSD) profiles and stable hydrogen bonding patterns. Gibbs free energy changes (ΔG_BFE &lt; 0) confirmed the sustained thermodynamic spontaneity of complex formation reactions where the values ranged from −39.88 to −26.66 kcal/mol. Pharmacokinetic predictions <em>via</em> pkCSM indicated favorable drug-likeness and ADMET profiles. These preliminary <em>in silico</em> findings highlight the strong potential of top five artopetelin flavonoids as PPARδ activators for type 2 diabetes management, underscoring their promise as plant-derived therapeutic agents and warranting further experimental validation.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109105"},"PeriodicalIF":2.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144255252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Modelling of the structural, phase stability, electronic, optical, and elastic behaviour of layered perovskites Rb2AgAsM6 (M = Cl and F) halide materials for optoelectronics Devices","authors":"Muhammad Khuram Shahzad ,&nbsp;Shoukat Hussain ,&nbsp;Abhinav Kumar ,&nbsp;Bhavesh Kanabar ,&nbsp;Suhas Ballal ,&nbsp;Kattela Chennakesavulu ,&nbsp;Vivek Kumar Pandey ,&nbsp;Binayak Pattanayak ,&nbsp;Ankit D. Oza ,&nbsp;Faiza Benabdallah","doi":"10.1016/j.jmgm.2025.109109","DOIUrl":"10.1016/j.jmgm.2025.109109","url":null,"abstract":"<div><div>The computational modeling of Rb₂AgAsM₆ (M = Cl and F) double perovskite halides is thoroughly examined in this work using the DFT model. Rb₂AgAsM₆ compounds ensured their prospective utility by meeting stability requirements for cubic structures. Formation (−817.951, −925.63) eV/atoms, cohesive (817.951, 925.63) eV/atoms energy, and tolerance factor (0.89, 0.78) of the compounds Rb₂AgAsM₆ (M = Cl and F) are measured for structural and thermal stability. Using the GGA-PBE approx., We found that the indirect electronic band gaps of Rb₂AgAsM₆ (M = Cl and F) fall between 1.34 eV and 2.29 eV. These values show that because of the strong spin-orbit coupling from heavy cations, the indirect band gaps of compounds fall inside the visible region. The Rb₂AgAsM₆ (M = Cl and F) compounds have mechanical Born stability, according to the calculated bulk modulus (41.254, 19.851) GPa. We found that when photon energy (eV) is applied to the Rb₂AgAsM₆ (M = Cl and F) compounds, the complex dielectric function promotes the greatest electron transition and absorption efficiency. These results highlight the potential of double perovskites made of Rb₂AgAsM₆ compounds for energy applications. According to DFT analysis, our study demonstrates the stability and advantageous characteristics of Rb₂AgAsM₆ (M = Cl and F) double perovskites. These findings underscore the potential of Rb₂AgAsM₆ (M = Cl and F) perovskites as environmentally friendly materials for advanced solar cells, optoelectronic devices, and next-generation technologies.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109109"},"PeriodicalIF":2.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144255254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The simpler the better? Enthalpies of formation and entropies of short-chain chlorinated paraffins by ab initio, DFT, group additivity and semiempirical approximations","authors":"Artem V. Chaikin ,&nbsp;Timofey P. Rozov ,&nbsp;Alexander S. Ryzhako ,&nbsp;Andrey D. Moshchenkov ,&nbsp;Arseniy A. Otlyotov ,&nbsp;Yury Minenkov","doi":"10.1016/j.jmgm.2025.109106","DOIUrl":"10.1016/j.jmgm.2025.109106","url":null,"abstract":"<div><div>An automated reaction-based approach coupled with DLPNO-CCSD(T)/CBS calculations was used to derive enthalpies of formation (Δ_f<em>H</em>⁰) of 32 short-chain chlorinated paraffins (SCCPs) containing 10–13 C atoms and 3–11 Cl atoms. Absolute entropies (<em>S</em>) were obtained using B3LYP-D3(BJ)/def2-TZVP optimized geometries and vibrational frequencies in the framework of the modified and scaled rigid rotor – harmonic oscillator (msRRHO) approximation. Conformational corrections to entropies were estimated using the CREST program and GFN<em>n</em>-xTB/FF methods. Examination of the performance of fast semiempirical methods reveals them to be suitable for the express evaluation of molecular entropies (mean unsigned deviation MUD_RM1 = 2.3 cal mol⁻¹ K⁻¹), while only PM6 method reproduces reference Δ_f<em>H</em>⁰ with MUD_PM6 = 2.4 kcal mol⁻¹, approximately within the estimated average error limits (2.8 kcal mol⁻¹). In contrast, simple Benson's group additivity method (GA) yields Δ_f<em>H</em>⁰ values with MUD_GA = 0.8 kcal mol⁻¹ but turns out to significantly overestimate entropies with MUD_GA = 20.4 cal mol⁻¹ K⁻¹. The obtained datasets of reliable Δ_f<em>H</em>⁰ and <em>S</em> values can be used for the further development of fast and efficient methods for the gas-phase thermochemistry evaluations of medium-sized molecules with rich conformational landscapes.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109106"},"PeriodicalIF":2.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144242416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational insights into substrate-assisted citrullination mechanisms of PAD2 isozyme: A comparative analysis of reaction pathways","authors":"Erdem Çiçek ,&nbsp;İpek Munar ,&nbsp;Sesil Agopcan Çınar ,&nbsp;Sinan Başçeken ,&nbsp;Gerald Monard ,&nbsp;Viktorya Aviyente ,&nbsp;Fethiye Aylin Sungur","doi":"10.1016/j.jmgm.2025.109107","DOIUrl":"10.1016/j.jmgm.2025.109107","url":null,"abstract":"<div><div>Citrullination, catalyzed by protein arginine deiminase enzymes, involves the conversion of peptidyl-arginine to peptidyl-citrulline, disrupting protein interactions and leading to functional alterations. Despite the experimental studies on PAD2 indicating calcium dependence and substrate specificity, the catalytic mechanism remains contentious, with conflicting evidence regarding the roles of active site residues such as Cys647 and His471. The present study is an expansion of prior molecular dynamics simulations that investigated the dynamics of the enzyme PAD2, which indicated that Asp473 may function as a general acid/base, thereby challenging the experimentally proposed pathways. To further elucidate this controversial issue, quantum mechanical methods were employed to examine the protonation states of key residues and their roles in catalysis. Herein, three different pathways have been studied for the substrate-assisted citrullination mechanism of PAD2 isozyme using a model structure that includes the active site residues Asp351, His471, Val472, Asp473, and Cys647 and a water molecule. The highest barriers for two of the designed mechanisms, RM1 and RM3 are comparable: the choice of a single mechanism is not possible since the differences in barriers fall within the error margins in DFT calculations. These findings offer insights into PAD2's enzymatic activity, thereby advancing our understanding of its biological significance.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109107"},"PeriodicalIF":2.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144242417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive investigation of structural, mechanical and optoelectronics attributes of M2AsC (M = Zr, Hf, Ta, W) MAX phase carbides: A DFT investigation","authors":"Mubashar Ali ,&nbsp;Zunaira Bibi ,&nbsp;Shamsa Kanwal ,&nbsp;Tehreem Fatima ,&nbsp;Muhammad Raheel ,&nbsp;Abdul Farhan Khan ,&nbsp;Muhammad Kaleem","doi":"10.1016/j.jmgm.2025.109102","DOIUrl":"10.1016/j.jmgm.2025.109102","url":null,"abstract":"<div><div>This research utilizes first-principles calculations to systematically investigate the phase stability, mechanical properties, and optoelectronic characteristics of the M₂AsC (M = Zr, Hf, Ta, and W) MAX phase carbides. The phase stability of these M₂AsC compounds is evaluated through the computation of formation enthalpies, which demonstrates that all analyzed compounds exhibit both structural and thermodynamic stability. To evaluate mechanical stability, we calculated the elastic stiffness constants, confirming the mechanical robustness of the studied MAX phases. Furthermore, the calculated Pugh and Poisson ratios reveal a brittle nature for Hf₂AsC and Ta₂AsC materials, while Zr₂AsC and W₂AsC compounds display notably high B/G ratios, indicating superior hardness relative to the other compounds studied. The band structure and density of states analyses confirm a metallic character for all M₂AsC compounds. A prominent hybridization effect is identified between the d-orbitals of M and the p-orbitals of C, while the interaction between the p-orbitals of M and As is comparatively less significant. The presence of pseudogaps near the Fermi level is linked to the orbital hybridization involving M, As, and C atoms. Charge density difference maps further elucidate the strong covalent bonding between M and C atoms, contrasted by a relatively weaker bonding interaction with As atoms. Additionally, a comprehensive examination of optical properties reveals that the highest absorptivity occurs within the energy range of 7.5–20 eV. The optical spectra of the MAX phases span from 1.7 eV in the infrared region to 11 eV in the ultraviolet region, indicating their potential as effective energy absorbers in the UV spectrum. Overall, the distinctive properties exhibited by M₂AsC compounds suggest their viability for a broad spectrum of applications across diverse fields.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109102"},"PeriodicalIF":2.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144255253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing models and experimental structures of the GPR101 receptor: Artificial intelligence yields highly accurate models","authors":"Stefano Costanzi ,&nbsp;Lea G. Stahr ,&nbsp;Giampaolo Trivellin ,&nbsp;Constantine A. Stratakis","doi":"10.1016/j.jmgm.2025.109103","DOIUrl":"10.1016/j.jmgm.2025.109103","url":null,"abstract":"<div><div>Experimental structures solved through cryo-electron microscopy have recently been published for GPR101, a G protein-coupled receptor (GPCR) implicated in the genetic condition X-linked acrogigantism (X-LAG). Here, we compared these experimental structures with computational models that we previously published, including our internally developed homology models and third-party models generated through the AlphaFold2 and AlphaFold-Multistate artificial intelligence (AI) methods. Our analysis revealed considerable accuracy for both homology models and AI-generated models. However, it also revealed the general superiority of AI methods. Particularly noteworthy is the model generated by AlphaFold2, which captured with high fidelity various structural aspects, including the challenging second extracellular loop. Our previously published homology model of the GPR101-G_s protein complex, based on the β₂-adrenergic receptor, accurately predicted the binding mode of the G protein to the receptor. Moreover, this model predicted the structure of the sixth transmembrane domain (TM6) significantly more accurately than the others, including those built through AI methods, suggesting that homology modeling based on templates solved in complex with the G protein of interest might be the most reliable way of modeling this transmembrane domain. Lastly, our analysis revealed that our molecular dynamics simulations did not have a significant and consistent effect on the accuracy of the models, increasing the accuracy for some domains while decreasing it for others. This work provides insights into the relative strengths of different modeling approaches for our case study on GPR101. More broadly, when considered alongside other assessment studies, it contributes to the growing body of knowledge that can guide the modeling of GPCRs for which experimental structures are not yet available.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109103"},"PeriodicalIF":2.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein-based QM-CGMM","authors":"Yi Sun","doi":"10.1016/j.jmgm.2025.109081","DOIUrl":"10.1016/j.jmgm.2025.109081","url":null,"abstract":"<div><div>We present an approach to Coarse Grain (CG) the Molecular Mechanics (MM) region in a thermodynamically consistent approach when the region is a protein backbone. This approach is achieved, via using 4 beads on each amino acid residue to replicate the electrostatic field that it generates, followed by connecting them via a heterogeneous Elastic Network Model (heteroENM) force-field. We subsequently treat the boundary between the QM and CGMM regions using appropriate Lennard-Jones parameters. We apply this procedure to the classic Chorismate Mutase system, where the enzyme backbone in the MM region catalyzes the Claisen rearrangement in the QM region using Transition-Tempered metadynamics (TTMetaD) to obtain a converged Potential of Mean Force (PMF). The CGMM reveals a free energy barrier similar to the experimental value. This work demonstrates the potential of utilizing a CGMM forcefield to capture all-atom thermodynamic properties at a reduced cost.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109081"},"PeriodicalIF":2.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-function activity study of the unusual protein MAPK1-109aa encoded by the non-coding circular RNA hsa_circ_0004872","authors":"Jit Mondal ,&nbsp;Sima Biswas ,&nbsp;Sreekanya Roy ,&nbsp;Anirban Nandy ,&nbsp;Dipanjan Guha ,&nbsp;Angshuman Bagchi","doi":"10.1016/j.jmgm.2025.109098","DOIUrl":"10.1016/j.jmgm.2025.109098","url":null,"abstract":"<div><div>Circular RNAs are closed-loop single-stranded non-coding RNA molecules. Once considered as transcriptional junks, their physiological roles in the process of tumourigenesis have recently been being identified. In spite of belonging to the class of non-coding RNAs, some of them have distinct protein coding abilities. The circular RNA hsa_circ_0004872, which encodes the protein MAPK1–109aa, is one such example. This protein is associated with gastric cancer pathway, as, MAPK1–109aa can bind to MEK1 and inhibit the phosphorylation of MAPK1 and this further disturbs the downstream signalling and activation processes necessary for the onset of gastric cancer. However, the residue level details of the binding interactions of MAPK1-109aa and its partners are not yet available. Therefore, our aim is to delineate the structural details and folding pattern of the protein and provide insight on its mode of interactions with its binding partner, MEK1. Furthermore, we tried to determine whether MAPK1-109aa has its role in any pathway(s) other than gastric cancer. Through the technique of network analyses, we could predict that the protein is associated with the pathways that lead to conditions like neurodegenerations and others. This work is the first of its kind, which elucidates the residue-level pattern of interactions of MAPK1-109aa with MEK1 in gastric cancer onset as well as the association of MAPK1-109aa with other diseases. This work highlights the potential application of MAPK1-109aa as a therapeutic agent for the treatment of gastric cancer.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109098"},"PeriodicalIF":2.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144222497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Manipulating high Curie temperature of Sm/Ag doped ZnO monolayers by first-principles GGA+U study","authors":"Hao Yuan ,&nbsp;Yanfang Zhao ,&nbsp;Yuanbin Xiao ,&nbsp;Bing Yang ,&nbsp;Wei Ding ,&nbsp;Jian Lv","doi":"10.1016/j.jmgm.2025.109101","DOIUrl":"10.1016/j.jmgm.2025.109101","url":null,"abstract":"<div><div>This work studies the electronic structure, and magnetic properties of Sm/Ag doped ZnO monolayer by first-principles GGA + U calculations. The results show Sm-doped ZnO monolayer exhibits stable room temperature ferromagnetism with a high magnetic moment of 5.91 μB per unit. The total magnetic moment of the system is mainly contributed by Sm-4f, and the high Curie temperature results from the strong ferromagnetic coupling between the adjacent Sm atoms. The Ag-doped ZnO monolayers undergo magnetic quenching with the Ag doping concentration from 6.25 at.% to 12.5 at.%, which is extremely advantageous for designing and manufacturing magnetic switches. The ZnO monolayer shifts between the non-magnetic to the antiferromagnetic as the distance between neighboring two Ag atoms changes. In Sm-Ag co-doped ZnO monolayer, the Sm atom and Ag atom spin in opposite directions, and the magnetic moments partially cancel out, and the total magnetic moment of the system decreases. In addition, Sm/Ag mono-doped and Sm-Ag co-doped ZnO monolayer exhibited half-metallic behavior due to the impurity energy levels introduced in the bandgap by Sm/Ag dopant, and calculations of the formation energy show that dopants are prone to aggregate. This research may provide a reference for modifying the material properties of ZnO monolayers and designing nano-electronic and spintronic devices.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109101"},"PeriodicalIF":2.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combinatorial chemistry-driven In silico design and computational evaluation of covalent peptidomimetic SARS-CoV-2 main protease inhibitors via structure-based virtual screening and multivariate analysis","authors":"Alessia Bono ,&nbsp;Gabriele La Monica ,&nbsp;Federica Alamia ,&nbsp;Francesco Mingoia ,&nbsp;Annamaria Martorana ,&nbsp;Antonino Lauria","doi":"10.1016/j.jmgm.2025.109100","DOIUrl":"10.1016/j.jmgm.2025.109100","url":null,"abstract":"<div><div>The COVID-19 pandemic has underscored the urgent need for specific pharmacological treatments beyond existing vaccines. One of the most attractive targets for antiviral therapies development is the SARS-CoV-2 Main Protease (M^PRO), a key enzyme in viral life. The lack of M^PRO human homologs and its conservation rate among coronaviruses make this enzyme strategically important. Considering its mechanism of action, the catalytic cysteine residue (Cys¹⁴⁵) presents a prime target for covalent inhibition. Electrophilic warhead inhibitors, designed to react with this catalytic site, mimic the amide peptide bonds of the viral polyproteins, thereby facilitating their binding and subsequent inactivation of the enzyme. Their activity is further potentiated when incorporated into peptidomimetic structures. <em>In silico</em> approaches are gaining increasing importance in the search for effective COVID-19 treatments. In this view, this study focuses on developing an innovative <em>in silico</em> protocol for identifying anti-SARS-CoV-2 agents covalently targeting M^PRO. To this purpose, a combinatorial library of 450 peptidomimetic compounds with aldehydic warheads was generated, refined to 388 compounds through docking studies, and further evaluated for covalent binding capabilities, revealing that compounds <strong>9</strong>–<strong>14</strong>, <strong>16</strong>, and <strong>20</strong> exhibited significantly higher affinities compared to known inhibitors, even during a 200 ns dynamics simulation, thus affirming the validity of the adopted design strategy. Furthermore, this work takes the advantages of our in-house ligand-based tool, the Biotarget Predictor Tool, available in DRUDIT, integrated with both structure-based techniques and, interestingly, multivariate statistical analysis.</div></div>","PeriodicalId":16361,"journal":{"name":"Journal of molecular graphics & modelling","volume":"140 ","pages":"Article 109100"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144196115","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}