In silico pharmacology最新文献

{"title":"In-silico identification of COX-2 inhibitory phytochemicals from traditional medicinal plants: molecular docking, dynamics, and safety predictions.","authors":"Faranak Abdollahi, Farzin Hadizadeh, Sadegh Farhadian, Reza Assaran-Darban, Neda Shakour","doi":"10.1007/s40203-025-00407-4","DOIUrl":"https://doi.org/10.1007/s40203-025-00407-4","url":null,"abstract":"<p><p>Inflammation is an essential biological response that facilitates tissue repair and immune defense; however, chronic inflammation is associated with numerous pathological conditions, including cardiovascular diseases, autoimmune disorders, and cancer. Cyclooxygenase-2 (COX-2) is a key enzyme in this process, catalyzing the synthesis of pro-inflammatory prostaglandins, thus representing a critical target for anti-inflammatory therapies. Conventional COX-2 inhibitors, particularly non-steroidal anti-inflammatory drugs (NSAIDs), often have significant side effects, creating an urgent need for safer alternatives. This in-silico study evaluates the binding affinities of bioactive compounds from <i>Gmelina arborea</i>, <i>Coriandrum sativum</i>, <i>Glycyrrhiza glabra</i>, <i>Terminalia chebula</i>, <i>Solanum nigrum</i>, <i>Vernonia cinerea</i>, <i>Portulaca oleracea</i>, <i>Azadirachta indica</i>, and <i>Thespesia populnea</i> to the COX-2 receptor. Molecular docking and dynamics simulations identified solasonine, solamargine, rutin, and glycyrrhizin as having binding affinities ranging from - 9.40 to - 8.50 kcal/mol, exceeding that of the standard NSAID diclofenac (- 5.68 kcal/mol). While these docking results provide valuable insights, further <i>in-vitro</i> validation is necessary. Stability analysis of ligand-receptor complexes showed minimal structural fluctuations. Moreover, cardiotoxicity predictions indicated that solamargine, rutin, and glycyrrhizin present a lower risk compared to diclofenac. ADMET profiling highlighted favorable pharmacokinetic properties for rutin, suggesting its potential as a promising COX-2 inhibitor with a beneficial safety profile. Subsequent MM-GBSA calculations revealed binding free energy values of - 11.316 kcal/mol for rutin and - 35.190 kcal/mol for diclofenac, indicating strong binding interactions. Overall, this study underscores the potential of these natural compounds as safer alternatives in anti-inflammatory therapy, paving the way for future experimental validation and clinical application.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00407-4.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 3","pages":"133"},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12440849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular docking, molecular dynamics simulation, and ADME profiling of novel benzoxazolone-based OGT inhibitors.","authors":"Tanisqa Mall, Parteek Prasher, Macarena Loncón-Pavez, Sebastián Morales-Guerrero, Mousmee Sharma, Yorley Duarte, Flavia C Zacconi","doi":"10.1007/s40203-025-00422-5","DOIUrl":"https://doi.org/10.1007/s40203-025-00422-5","url":null,"abstract":"<p><p>This study presents a computational exploration of a new series of benzoxazolone-amino acid conjugates appended with amino acids as potential inhibitors of <i>O</i>-GlcNAc transferase (OGT), an enzyme of growing therapeutic interest that currently has only one well-established inhibitor, OSMI-4. To address the scarcity of effective and selective OGT inhibitors, the research evaluates both acid (b-series) and ester (a-series) forms of the ligands, aiming to balance binding affinity with favourable pharmacokinetic properties. Acid counterparts generally demonstrated superior binding affinities, while ester analogues were introduced as prodrug candidates to enhance lipophilicity, membrane permeability, and bioavailability. Molecular docking and molecular dynamics (MD) simulations revealed the stability and interaction dynamics of the ligand-protein complexes. Compounds such as 1b, 8b, 9b, and 12b exhibited consistent hydrogen bonding and salt-bridge interactions, maintaining low root-mean-square deviation (RMSD) and fluctuation (RMSF) values-indicators of stable binding and minimal conformational shifts. In contrast, ester counterparts such as 9a and 12a displayed higher flexibility and fewer interactions, supporting their potential role as deliverable prodrugs rather than optimal binding agents. Pharmacokinetic profiling via SwissADME confirmed the drug-likeness of selected compounds, indicating favourable solubility, gastrointestinal absorption, and peripheral tissue targeting without blood-brain barrier penetration. All analogues complied with Lipinski's Rule of Five, affirming their potential as drug candidates. Furthermore, the study identifies key interaction hotspots within the OGT binding pocket and establishes a clear structure-activity relationship (SAR), laying the groundwork for pharmacophore modelling and rational drug design. Overall, this study gives significant insights into the dual optimization of efficacy and bioavailability through esterification strategies and offers a promising foundation for the development of next-generation OGT inhibitors based on benzoxazolone scaffolds.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00422-5.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 3","pages":"134"},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12440838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic potential of <i>Andrographis paniculata</i> against Monkeypox virus targets-a computational insight.","authors":"Rashmi Sahu, Rajan Mariappan, Awanish Kumar, Arun Kumar Mahapatra, S Rajagopala, Prashant Kumar Gupta","doi":"10.1007/s40203-025-00423-4","DOIUrl":"10.1007/s40203-025-00423-4","url":null,"abstract":"<p><p>Monkeypox, a viral zoonotic disease caused by the monkeypox virus (MPXV), has recently become a significant global health threat due to increased human-to-human transmission. As of November 2023, the Mpox outbreak had impacted 116 countries worldwide, with a total of 92,783 confirmed cases and 171 reported deaths. With limited antiviral options available, natural plant-based compounds like <i>Andrographis paniculata</i> have shown promise for their antimicrobial and antiviral properties. This study explores the potential of bioactive compounds from <i>A. paniculata</i> against monkeypox viral targets through computational methods. Protein structures 4E90, 8B07, 8C9K, 8IZT and 8J8G were obtained from the Protein Data Bank (PDB), and molecular dynamic simulation studies were conducted using the Schrödinger Suite. Furthermore, the trajectory analysis assessed the stability and binding affinity of the ligand-protein complexes. The compounds andrographolide, luteolin, and andrographidin-A demonstrated strong binding interactions and stable protein-ligand complexes, along with favorable thermodynamic profiles, supporting their potential as promising therapeutic candidates for monkeypox treatment.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00423-4.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 3","pages":"130"},"PeriodicalIF":0.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12423014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145066913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of potent inhibitors against KRAS, its mutant G12R, allosteric and Switch-I/Switch-II site.","authors":"Vikas Yadav, Mohammad Kashif, Swati Sharma, Naidu Subbarao","doi":"10.1007/s40203-025-00415-4","DOIUrl":"10.1007/s40203-025-00415-4","url":null,"abstract":"<p><p>KRAS, a key member of the Ras family of GTPases, plays a crucial role in regulating cell growth, survival, and differentiation. Mutations in KRAS, such as G12R, are frequently linked to cancer, making it an important therapeutic target. Due to its smooth surface and strong nucleotide-binding affinity, KRAS has long been considered difficult to target with drugs. Recent advancements have identified new binding sites, including allosteric pockets and the Switch-I/Switch-II (SI/II) regions, which offer alternative strategies for drug development. In this study, a combination of computational techniques was used to identify potential inhibitors of KRAS and its G12R mutant. Virtual screening revealed four promising compounds NSC 374,037, NSC 655,101, V016-9984, and N060-0122 that outperformed known inhibitors such as Sotorasib in binding affinity. Molecular dynamics simulations confirmed the stability of these compounds within KRAS binding pockets, supported by favourable RMSD, RMSF, and radius of gyration values. Binding energy calculations showed that NSC 655,101 had the strongest affinity for wild-type KRAS while V016-9984 and N060-0122 were most effective at targeting the allosteric and SI/II sites respectively. Time-lagged Independent Component Analysis (TICA) provided critical insights into how these ligands modulate KRAS conformational dynamics, revealing ligand-specific effects on protein flexibility and stabilization of key conformations. These findings highlight the potential of these inhibitors as promising candidates for KRAS-targeted therapies. The results provide a strong basis for further experimental testing, bringing us closer to effective treatments for KRAS-driven cancers.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00415-4.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 3","pages":"131"},"PeriodicalIF":0.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12423349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145066899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phytocompounds of Honey mesquite (<i>Prosopis glandulosa</i>) and Lodhra (<i>Symplocos racemosa</i>) in the management of COVID-19 associated rheumatoid arthritis (CARA).","authors":"Gargi Sen, Indrani Sarkar, Sandipan Ghosh, Arnab Sen","doi":"10.1007/s40203-025-00419-0","DOIUrl":"10.1007/s40203-025-00419-0","url":null,"abstract":"<p><p>COVID-19 persists globally with profound social and economic consequences, and its complex interplay with other diseases makes it a syndemic. Rheumatoid arthritis (RA), a chronic autoimmune disorder, has shown increased incidence during the pandemic, with patients displaying higher susceptibility to COVID-19. This overlap prompted the hypothesis of '<i>COVID-19-associated rheumatoid arthritis (CARA)</i>'. The present study explores phytocompounds with anti-inflammatory and immunomodulatory properties as potential CARA therapeutics. Compounds from <i>Prosopis glandulosa</i> and <i>Symplocos racemosa</i>, both used in traditional medicine, were evaluated through molecular docking and simulation studies. Six inflammatory targets relevant to RA and COVID-19 -interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF), human leukocyte antigen DR4 (HLA-DR4), signal transducer and activator of transcription 4 (STAT4), and peptidyl arginine deiminase 4 (PAD4) were selected. Among the tested ligands, salidroside showed the strongest binding affinity, with energies of - 8.20 kcal/mol (IL-6), - 7.67 kcal/mol (TNF-α), - 8.53 kcal/mol (GM-CSF), - 8.80 kcal/mol (HLA-DR4), - 8.18 kcal/mol (STAT4), and - 7.91 kcal/mol (PAD4), indicating stable interactions. These findings suggest salidroside could modulate key inflammatory pathways and potentially reduce cytokine storms in COVID-19 patients. Existing RA and COVID-19 treatments often cause immunosuppression, increasing vulnerability to opportunistic infections (Datta et al in J Biomol Struct Dyn 41(8):3281-3294, 2022). Immunomodulatory phytocompounds like salidroside may offer safer, targeted alternatives without compromising immune defenses. However, this study is based on in silico analyses, and warrants in vitro and in vivo validation. Nevertheless, present work may represent an important step towards novel therapeutic strategies for COVID-19 Associated Rheumatoid Arthritis (CARA).</p><p><strong>Graphical abstract: </strong></p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 3","pages":"129"},"PeriodicalIF":0.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-silico insights into <i>Terminalia citrina</i> targeting OmpA: an approach to combat multidrug resistance in <i>Acinetobacter baumannii</i>.","authors":"Romen Meitei Lourembam, Jobina Rajkumari, Arunkumar Singh Koijam, Sushmita Bhattacharya, Sulagna Basu, Sunil S Thorat, Sarangthem Indira Devi","doi":"10.1007/s40203-025-00411-8","DOIUrl":"10.1007/s40203-025-00411-8","url":null,"abstract":"<p><strong>Abstract: </strong>The rise of multidrug-resistant <i>Acinetobacter baumannii</i> poses significant challenges in hospital settings. This study evaluates the antimicrobial potential of the aqueous extract of <i>Terminalia citrina</i> (AETC) against <i>A. baumannii</i> strain AB0014, isolated from a preterm neonate presenting sepsis. The minimum inhibitory concentration (MIC) was determined using the microdilution method. Outer Membrane Protein A (OmpA) was targeted due to its role in bacterial structural integrity and pathogenicity. A protein-protein interaction (PPI) network was constructed using literature data and validated via the STRING database. Molecular docking results from AutoDock Vina and AutoDock 4.0 were further analysed, and the ligands were ranked using statistical tools such as ANOVA. AETC exhibited potent antimicrobial activity, with a 56 mm zone of inhibition and an MIC of 0.059 µg/mL. LC-MS analysis identified twelve major phytocompounds. Network analysis confirmed OmpA as a key regulatory hub in antibiotic resistance, interacting with β-lactamase genes (BlaR1, AmpC), efflux pumps (AdeB, MexR), and pathways associated with multidrug resistance. Further analysis revealed OmpA's dominance (degree = 7, betweenness = 0.85), with a low clustering coefficient (0.059), indicating network vulnerability upon inhibition. PCR confirmed the presence of <i>ompA</i> in <i>A. baumannii</i> AB0014. Lipinski's Rule of Five analysis indicated that 83.33% of the phytocompounds present in the AETC met drug-likeness criteria, suggesting high bioavailability. Molecular docking identified Terminalin as the most promising inhibitors, with strong binding affinities. Further, molecular dynamics simulations demonstrated the ability to interact effectively with OmpA while maintaining or enhancing its structural dynamics. This study highlights the antimicrobial potential of AETC and its ability to target OmpA-mediated resistance in <i>A. baumannii</i>, offering a promising therapeutic strategy.</p><p><strong>Graphical abstract: </strong></p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 3","pages":"124"},"PeriodicalIF":0.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network pharmacology and in silico analysis of <i>Cucumis melo</i> phytochemicals targeting ER stress in diabetic nephropathy.","authors":"Mohammed Nazish Quasmi, Jiten Singh, Sanjay Yadav, Dinesh Kumar, Pawan Gupta, Ashok Jangra","doi":"10.1007/s40203-025-00406-5","DOIUrl":"10.1007/s40203-025-00406-5","url":null,"abstract":"<p><strong>Abstract: </strong>This study aims to identify the molecular mechanism of <i>Cucumis melo</i> (CM) in regulating endoplasmic reticulum stress (ER stress) associated with diabetic nephropathy (DN) by using network pharmacology and bioinformatic studies. The targets of CM and target of ER stress and DN were obtained from various online databases. Top targets for CM regulating ER stress in DN were identified using PPI network. KEGG and GO analysis were used to examine the hub genes from a macro viewpoint. The present study identified 41 potential active phytochemicals, 212 potential therapeutic targets and 15 hub genes (targets). The primary targets which were closely associated with the pathways that are primarily involved in DN and ER stress were AKT1, EGFR and SRC. Furthermore, top 2 phytochemicals (eriodictyol and curcumin) and top 3 targets (AKT1, EGFR and SRC) were selected based on their degree score for molecular docking studies. It was observed that eriodictyol and curcumin had significant binding affinity potential against these targets (- 9.8 kcal/mol and - 9.5 kcal/mol against AKT-1, - 8.2 kcal/mol and - 7.6 kcal/mol against EGFR and - 8.8 kcal/mol and - 8.8 kcal/mol against SRC, respectively), along with the good binding interactions with key residues. Further, validation of docking results in molecular dynamic simulations was elucidated that eriodictyol and curcumin were had significant stability and binding ability against these targets (AKT1, EGFR and SRC) as compared to standard drug, but need to be tested experimentally. This research reveals the potential targets and pathways which can be targeted in DN treatment by regulating ER stress using CM.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00406-5.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 3","pages":"126"},"PeriodicalIF":0.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico framework about prediction of collagen-derived matrikine generation and its ligand function binding to integrin [Formula: see text] for malignancy of colon cancer.","authors":"Yun Shin, Jin-Ku Lee","doi":"10.1007/s40203-025-00417-2","DOIUrl":"10.1007/s40203-025-00417-2","url":null,"abstract":"<p><p>Colon cancer accounts for the second leading cause of cancer-associated death worldwide. Since the metastasis contributes to its malignancy, targeting the extracellular matrix (ECM) remodeling is critical for its therapy. Most research had focused on the native form of the structural ECM proteins, termed core matrisomes, to find out the relationship of the TME to colon cancer progression. This study computationally predicted the generation and function of their bioactive fragments, termed matrikines, as ligands to their cognate integrin receptors. Type I (COL1A1 and COL1A2) and III (COL3A1) as the precursor, Membrane type-1 matrix metalloproteinase (MMP14) as the cleavage enzyme, integrin [Formula: see text] (macrophage-1 antigen, Mac-1) as the receptor, and caldesmon (CALD1) as the downstream effector were designated as each candidate. After the computational cleavage of the collagen, 3D structure prediction of the generated fragments and the docking simulation with the integrin receptor expected two fragments, each from COL1A1 and COL3A1, to be the significant ligand for binding to [Formula: see text]I domain of integrin [Formula: see text]M subunit. They commonly consist of [Formula: see text]-sheet and loop as the major motifs, which also belong to the binding main of the previously established ligands, such as ICAM-1 and pleiotrophin. The structural similarity between the binding domains from each ligand might support our framework for the overall prediction. Given the integrin [Formula: see text] as the well-known cell-surface marker of the phagocytic cells, our study suggests targeting the proposed candidates for immunotherapy during the colon cancer metastasis.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00417-2.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 3","pages":"127"},"PeriodicalIF":0.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-guided design and triplicate molecular dynamics evaluation of mutant peptide inhibitors targeting SARS-CoV-2 main protease (Mpro).","authors":"Ankita Bhagat, Lakshmi Mounika Kelam, Nilanjan Samanta, M Elizabeth Sobhia","doi":"10.1007/s40203-025-00409-2","DOIUrl":"10.1007/s40203-025-00409-2","url":null,"abstract":"<p><p>The global health crisis caused by SARS-CoV-2 underscores the urgent need for effective antiviral therapeutics. The SARS-CoV-2 main protease (Mpro) is a crucial enzyme in viral replication, making it a prime target for drug development. In this study, we designed and evaluated peptide inhibitors targeting Mpro by introducing systematic mutations in the Nsp10/11 cleavage site peptide (QLMPER). A library of 214 mutant peptides was generated, from which 25 single-mutant and 70 multi-mutant peptides exhibited strong interactions with Mpro. The top four multi-mutant peptides were selected based on docking scores, molecular dynamics (MD) simulations, and MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) binding free energy calculations. Triplicate 100 ns molecular dynamics simulations assessed the stability of these complexes, revealing that M3 exhibited the highest structural stability and lowest binding free energy (- 34 kcal/mol), outperforming the wild-type peptide (- 4.28 kcal/mol). Computational infrared (IR) spectral analysis confirmed structural modifications induced by mutations, while HOMO-LUMO analysis indicated enhanced reactivity for M3 (FLFPFR). These findings suggest that M3 (FLFPFR) is a promising candidate for SARS-CoV-2 inhibition, highlighting the potential of rationally designed peptide inhibitors in antiviral drug discovery.</p><p><strong>Graphical abstract: </strong>Computational workflow for design and evaluation of mutant peptides against SARS-CoV-2 Mpro, highlighting the workflow, key interactions, and improved binding of mutants at S2 and S3/S4 subsites.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00409-2.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 3","pages":"125"},"PeriodicalIF":0.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering curcumin's differential inhibition of KPC-3, L2, and CTX-M-15 β-lactamases through binding energetics and structural dynamics.","authors":"Rafiullah Shirzadi, Abdul Musawer Bayan, Sayed Hussain Mosawi","doi":"10.1007/s40203-025-00421-6","DOIUrl":"10.1007/s40203-025-00421-6","url":null,"abstract":"<p><p>The rise of β-lactamase-mediated resistance in Gram-negative pathogens has created an urgent need for novel inhibitors to preserve antibiotic efficacy. This study explores the potential of curcumin, a natural polyphenol with known antimicrobial properties, as a broad-spectrum inhibitor of class A serine-β-lactamases (SBLs) through comprehensive computational analysis. Using molecular docking, 200 ns molecular dynamics simulations, and binding energy calculations, we investigated curcumin's interactions with three clinically important SBLs: KPC-3, CTX-M-15, and L2. Our results demonstrate curcumin's strong binding affinity across all three enzymes, with particularly potent inhibition of L2 (ΔG = - 7.67 kcal/mol) driven by favorable van der Waals interactions (- 115.03 kJ/mol) and an extensive hydrogen bonding network involving catalytic residues Ser70 and Ser130. Molecular dynamics simulations revealed distinct inhibition mechanisms: L2 showed global stabilization with reduced flexibility (15-20% decrease in RMSF); CTX-M-15 exhibited balanced binding with moderate solvation effects; while KPC-3 displayed local active-site stabilization despite overall structural destabilization, evidenced by increased radius of gyration. These findings highlight curcumin's remarkable adaptability as a multi-target β-lactamase inhibitor, capable of employing enzyme-specific strategies while maintaining core inhibitory interactions. The study provides crucial molecular insights that could guide the development of curcumin-derived adjuvants to combat β-lactam resistance, bridging traditional medicine and modern drug discovery approaches to address this critical public health challenge.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s40203-025-00421-6.</p>","PeriodicalId":94038,"journal":{"name":"In silico pharmacology","volume":"13 3","pages":"128"},"PeriodicalIF":0.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}