In silico pharmacology最新文献

This study explores the potential of selected natural products from Harungana madagascariensis (namely: harunganin anthrone, madagascin anthrone, harongin anthrone, harunmadagascarins-A, harunmadagascarins-B, kenganthranol-A, kenganthranol-B, kenganthranol-C, harunganol-A, harunganol-B, harunganol-D, harunganol E, harunganol-C, kengaquinone, madagascin, physcion, chrysophanol, madagascol, vismiaquinone-A, vismiaquinone-B, vismiaquinone-C, euxanthone, cadensin C, friedelan-3-one, lupeol, betulinic acid, kaempferol-3-O-β-D-glucopyranoside and methyl-3-formyl-2,4-dihydroxy-6-methyl benzoate) as inhibitors of bio-film formation response regulator (BfmR), a key virulence-associated response regulator in Acinetobacter baumannii (one of the ESKAPE pathogens).We employed integrative computational approach encompassing molecular docking, drug-likeness screening, ADMET profiling, molecular dynamics (MD) simulations, and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) free energy calculations for this assessment. Molecular docking indicated strong binding affinities at the BfmR homodimer interface, with the obtained docking scores surpassing that of the reference antibiotic, ofloxacin. Five top-performing compounds-harunganol-B, madagascin, madagascol, vismiaquinone-B and vismiaquinone-C were identified as potential inhibitors which showed properties compliant with Lipinski's Rule of Five. They also showed favorable gastrointestinal absorption and blood-brain barrier permeability profiles, as revealed by the BOILED-Egg model. MD simulations confirmed the structural stability of ligand-protein complexes, showing minimal RMSD and enhanced compactness and residue rigidity upon ligand binding. MM/PBSA analyses further supported the stability of the complexes, with harunganol-B demonstrating the most favorable binding free energy (ΔG_bind = - 50.12 kcal/mol). Overall, the computational data obtained underscore the promising inhibitory potential of these compounds, particularly harunganol-B, and highlighted their suitability for future in vitro and in vivo validation as lead scaffolds in anti-A. baumannii drug development.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00558-y.

Staphylococcus aureus, a major human pathogen, exhibits strong survival abilities both inside and outside host cells. The increasing prevalence of antibiotic-resistant strains presents a major challenge to modern medicine. Bioactive compounds from medicinal plants represent a potential alternative, owing to their diverse secondary metabolites. This study employed in silico docking and molecular dynamics simulations to identify bioactive compounds from medicinal plants targeting the virulence protein clumping factor A (ClfA) of S. aureus. Phytocompounds from Breynia retusa, Hemigraphis alternata, Imperata cylindrica, Oldenlandia corymbosa, Sida rhombifolia, Scoparia dulcis, Tephrosia purpurea, and Wrightia tinctoria were screened for pharmacokinetic properties, followed by molecular docking and dynamics simulations. Indirubin from W. tinctoria exhibited strong binding affinity for ClfA, with stable interactions confirmed by molecular dynamics simulations. Antibacterial assays using fresh and dry W. tinctoria leaf extracts demonstrated significant inhibition of S. aureus. GC-MS analysis identified 50 bioactive compounds, further supporting the plant's potential as a natural antimicrobial source. These findings highlight W. tinctoria, particularly indirubin as a promising candidates for developing anti-staphylococcal and wound-healing agents, warranting further in vivo validation.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00545-9.

Marburg virus (MARV) is classified as a risk group 4 pathogen by the WHO due to its high fatality rates, frequent person-to-person transmission, and lack of approved vaccines or treatments. This highlights the need for a universally effective MARV vaccine. In this study, we employed computational bioinformatics methods to analyze conserved sequences of the VP30 transcriptional activator, using databases and bioinformatics tools. Amino acid sequences were sourced from NCBI, and antigenicity was assessed using Kolaskar, Tongaonkar, and VaxiJen servers. B and T cell epitopes were identified using ABCPred and the Immune Epitope Database, providing insights into potential immunogenic regions. The VP30 protein, crucial in both physiological and pathological processes, emerged as a promising target for vaccine development. Key epitopes from VP30, including IGLPCTDGL and PCKIGLPCTIGLPCTD, showed efficacy as T and B cell epitopes. We designed a multi-epitope vaccine incorporating these epitopes, demonstrating favorable physicochemical and immunological properties. Molecular dynamics simulations confirmed that both mono- and multi-epitopes improve the vaccine's therapeutic potential. Our analysis suggests the proposed vaccine candidate could trigger an immune response against MARV. However, experimental validation is needed to confirm its immunomodulatory properties and effectiveness.

In this study, a series of indole-based derivatives (2a-f) was synthesized, followed by a Mannich base reaction from the starting materials, substituted phenylhydrazine and substituted acetophenone, in glacial acetic acid. All the synthesized derivatives were characterized by IR, NMR, Mass and screened for anticonvulsant activity using the maximal electroshock model. Among all, 2b, 2c and 2e exhibited potent anticonvulsant activity as compared to standard drug phenytoin sodium. In our study, we carried out an in-silico study against GABA receptor, and the AMPA-sensitive glutamate. Docking study revealed that 2b, 2c, 2e showed good binding energy against AMPA receptor. Among the six synthesized compounds 2b, 2c, and 2e were found to possess an optimum to excellent in- silico ADME properties. Our results showed that substituting a 2-phenylindole derivative also increases the therapeutic value of the 2-phenylindole core, which is needed for the discovery of a potent anticonvulsant agent.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00517-z.

Human coronavirus infections, particularly those caused by SARS-CoV-2, remain a significant public health concern. Researchers are actively exploring new antiviral compounds, including those derived from marine natural products. This study investigates fucoxanthin (FX) and its metabolites, fucoxanthinol (FXOH) and amarouciaxanthin A (AXA), as potential inhibitors of the SARS-CoV-2 nucleocapsid phosphoprotein (NP) using molecular docking. Molecular dynamics simulations were performed for 100 ns, along with the reference drug, ribavirin, for comparative purposes. Compared to ribavirin (- 5.870 kcal/mol), FXOH (- 5.662 kcal/mol), AXA (- 5.189 kcal/mol), and FX (- 4.594 kcal/mol), the binding energies were low. RMSD analysis revealed that the NP-ribavirin (1.4-3.8 Å) exhibit a more rigid protein confirmation. In constant, the NP-FX (2.4-4.8 Å), and NP-FXOH (2.5-4.5 Å) showed moderate fluctuations, reflecting the inherent flexibility of the protein. cDFT analysis (HOMO &LUMO) revealed that FX had higher electronic reactivity and charge-transfer capability, whereas FXOH showed greater electronic stability. From these observations, the FX and FXOH remained in the binding site during the MD simulation, and they can be used as an antiviral drug formulation. However, this study is limited to computational prediction, and further in vitro and in vivo investigations are needed to validate the efficacy, safety, and pharmacokinetic properties of ligands.

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Oral squamous cell carcinoma (OSCC) is a significant global health concern, with approximately 377,000 new cases diagnosed annually worldwide. Despite advances in treatment, OSCC remains a leading cause of cancer-related morbidity and mortality, particularly in regions with high prevalence such as Asia and Oceania. In order to identify potential drug targets for OSCC, this study employed an integrative in silico pharmacology strategy. Nineteen GEO transcriptomic datasets (435 samples) were analyzed, 580 significantly overexpressed genes (logFC > 2.5). Network and enrichment analyses highlighted CASQ1 (calsequestrin 1), a calcium-binding protein, as a hub gene within a sarcomeric cluster implicated in epithelial-mesenchymal transition and OSCC progression. To explore its therapeutic potential, molecular docking and 500 ns molecular dynamics (MD) simulations were performed with standard chemotherapeutics, 5-fluorouracil and docetaxel. 5-fluorouracil exhibited strong binding affinity (- 7.225 kcal/mol) and stable conformational dynamics with CASQ1, while docetaxel showed more flexible but persistent binding. These results suggest that CASQ1 is a previously unrecognized drug-interactable target in OSCC and may represent a novel pharmacological vulnerability. Overall, this study demonstrates how integrative computational approaches, spanning gene expression profiling to drug-target interaction modeling, can accelerate target discovery and inform therapeutic strategies in oncology.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00554-2.

Human metapneumovirus (hMPV) is one of the potential pandemic pathogens, and it is a concern for elderly subjects and immunocompromised patients. There is no vaccine or specific antiviral available for hMPV. We conducted an in-silico study to predict initial antiviral candidates against human metapneumovirus. Our methodology included protein modeling, stability assessment, molecular docking, molecular simulation, analysis of non-covalent interactions, bioavailability, carcinogenicity, and pharmacokinetic profiling. We pinpointed four plant-derived bio-compounds as antiviral candidates. Among the compounds, apigenin showed the highest binding affinity, with values of - 8.0 kcal/mol for the hMPV-F protein and - 7.6 kcal/mol for the hMPV-N protein. Molecular dynamic simulations and further analyses confirmed that the protein-ligand docked complexes exhibited acceptable stability compared to two standard antiviral drugs. Additionally, these four compounds yielded satisfactory outcomes in bioavailability, drug-likeness, and ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) and STopTox analyses. This study highlights the potential of apigenin and xanthoangelol E as an initial antiviral candidate, underscoring the necessity for wet-lab evaluation, preclinical and clinical trials against human metapneumovirus infection.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00539-7.

Src homology region 2 -containing protein tyrosine phosphatase 2 (SHP2) is an oncoprotein and a promising target for cancer treatment. Efforts to develop SHP2 allosteric inhibitors, such as SHP099, have laid the foundation for SHP2-targeted therapeutics. However, there are few SHP2 allosteric inhibitors have reached to clinical trials up to date. SHP099, despite its high potency, has off-target effects on the human ether-a-go-go related gene (hERG) channel, increasing cardiovascular toxicity risk due to its highly basic amine group. To address these challenges, understanding the molecular interactions between SHP2 allosteric inhibitors and SHP2 is essential for advancing drug development. In a previous study, an in-silico structure-based screening identified neutral SHP2 inhibitors, including C8. This study analyzed the binding modes of ionized and neutral SHP2 allosteric inhibitors under physiological and acidic pH conditions using constant pH molecular dynamics (cpHMD) simulations. SHP099 and C8 exhibited lower free binding energies with SHP1 compared to SHP2, confirming their specificity for SHP2. The protonated tertiary amine group in SHP099 contributed significantly to ligand stability and binding to SHP2, which was not observed with the neutrally charged allosteric inhibitor (C8). Furthermore, SHP099's binding interactions with SHP2 were pH-dependent, with acidic pH conditions showing the highest binding affinity. These findings provide insights into the molecular interactions of SHP2 allosteric inhibitors under physiologically relevant conditions, which will guide the optimization of the structural design of pyrazine-class SHP2 allosteric inhibitors.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00551-x.

Dracaena reflexa is a medicinal plant traditionally used for various therapeutic purposes. This study focused on the isolation, characterization and anti-viral evaluation of bioactive constituents from its stem (dichloromethane extract) and leaves (ethanol extract). Chromatographic techniques yielded two compounds: Compound (1) is 3-(6',8'-dimethoxydodecyl)-4-(4-hydroxyphenyl)-1H-pyrrole-2,5-dione, a novel alkylated pyrrole derivative and Compound (2) is 3,3',4',5,7-pentahydroxyflavon, a flavonoid reported for the first time in Dracaena reflexa. Structural elucidation was conducted using UV-Vis, FTIR, ¹H-NMR, ¹³C-NMR and mass spectrometry. Molecular docking studies targeting SARS-CoV-2 main protease (Mpro) and spike protein (Spro) revealed that Compound (2) exhibited stronger binding affinities (- 7.92 and - 8.47 kcal/mol, respectively) compared to Compound (1) (- 4.85 and - 6.60 kcal/mol) and was comparable to the reference drug, ivermectin. In silico ADME analysis showed that both compounds conformed to Lipinski's Rule of Five and displayed favorable pharmacokinetic properties, including good solubility, lipophilicity and gastrointestinal absorption. Compound (2) also exhibited better drug-likeness and bioavailability characteristics. These findings suggest that both compounds, particularly Compound (2), hold promise as lead candidates for the development of antiviral agents against SARS-CoV-2. Further in vitro and in vivo studies are recommended to validate their therapeutic potential.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00555-1.

Dental caries is a prevalent chronic infection caused by tooth-adherent cariogenic bacteria, mainly Streptococcus mutans, which demineralize tooth structure and lead to plaque formation. The present study evaluated the potential of Barleria cuspidata leaf extract (BCLE) to combat tooth decay by investigating its effects on S. mutans, a major contributor to dental caries, using both in vitro and in silico approaches. BCLE strongly inhibited the growth of S. mutans, showing a zone of inhibition of 17.4 mm at 150 µ g/mL, with a minimum inhibitory concentration (MIC) of 1 mg/mL. At twice the MIC (2 mg/mL), it exhibited bactericidal effects, prevented acid production, reduced cell surface hydrophobicity, and inhibited biofilm formation. Thirty-six major compounds revealed from Gas chromatography-mass spectrometry results of BCLE were subjected to molecular docking with the receptors, dextranase, N-terminal, and central regions comprising the third A-repeat through the first P-repeat (A3VP1) of antigen I/II, glucan binding protein C, deoxycytidylate deaminase, and dextran glucosidase that coordinates with the demineralization of tooth structure and plaque formation. Out of thirty-six compounds docked, the top fourteen showed no violations for the drug-likeness feature except monoethylhexylphthalate, pentadecanoic acid, and 3-hydroxy carbofuran phenol. Among them, Octadecanedioic acid represented the highest inhibition with deoxycytidylate deaminase (SmdCD) (PDB ID: 5C2O), and the complex, further analyzed for molecular dynamic simulation for 100ns, was found to be stable from 60-100ns with strong ionic and hydrogen bond interactions. Thus, the study suggested that the anti-cariogenic effect of BCLE would be beneficial in exploring the co-existence of plant extract and inventing novel herbal medicines to enhance caries protection.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00529-9.