In silico pharmacology最新文献

Background: Lymphatic filariasis, or elephantiasis, is a neglected tropical disease caused by filarial nematodes such as Brugia malayi. Current antifilarial drugs-diethylcarbamazine (DEC), albendazole, and ivermectin form the basis of mass drug administration (MDA) programs for lymphatic filariasis. While effective against microfilarial stages, these agents show little or no macrofilaricidal activity, necessitating repeated treatment rounds to interrupt transmission. Growing evidence of reduced efficacy and emerging resistance further threatens the sustainability of these regimens. Thioredoxin reductase (TrxR) and β-tubulin are critical for parasite survival: TrxR maintains redox balance and protects against oxidative stress, while β-tubulin supports cytoskeletal integrity, intracellular transport, and cell division. Their combined roles in stress adaptation and structural stability make them compelling dual targets. This study employed structure-based virtual screening, molecular docking, and molecular dynamics simulations (MDS) to identify novel thiol-based inhibitors against both proteins.

Results: A total of 467 compounds were virtually screened, leading to the identification of seven lead candidates with superior docking scores (- 8.5 to - 4.0 kcal/mol) compared to the standard drug albendazole (- 5.3 to - 4.5 kcal/mol). Notably, compound 15 demonstrated the strongest binding affinity coupled with an optimal toxicity profile. Pharmacokinetic analysis using ADME assays confirmed drug-likeness and oral bioavailability of the top ligands, with minimal Lipinski's rule violations. Molecular dynamics simulations exceeding 100 ns revealed sustained stability of the protein-ligand complex, which was further supported by RMSD and RMSF analyses, demonstrating conformational stability. Principal interactions comprised hydrogen bonding, hydrophobic contacts, and π-stacking with conserved residues within the active sites of the target proteins.

Conclusion: The integrated in silico approach combining docking, pharmacokinetic profiling, and MDS successfully identified potent thiol-based ligands with high affinity for β-tubulin and TrxR in B. malayi. Among these, HI/CYR/TH-15 emerged as the most promising lead. These findings provide a foundation for the development of next-generation anti-filarial therapies targeting multiple life stages, warranting further in vitro and in vivo validation to confirm therapeutic potential.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00474-7.

Diabetic peripheral neuropathy is a devasting microvascular complication that is associated with chronic pain. Currently transient receptor potential vanilloid 1 (TRPV1), serotonin transporter (SERT) and voltage gated calcium channel (VGCC) are considered as potential targets for neuropathic pain management. The present study investigated the interactions of terpinolene with pain targets by molecular docking and simulation studies. The structure and physicochemical properties of terpinolene were obtained from the PubChem, SwissADME and pkCSM databases respectively. The crystallographic structures of the molecular targets retrieved from PDB database (5IS0, 6AWO and 7MIY) were used for docking analysis using Schrodinger software. Docking studies revealed that terpinolene docks well with pain targets related to neuropathy. Molecular dynamics (MD) simulations of protein-ligand complexes were carried out using CABS-flex V2.0 and the iMOD server. These tools were used to assess the root-mean-square fluctuations (RMSFs) and the stability of the protein structures, respectively. The findings indicated that the docked models exhibited greater flexibility and stability with terpinolene. Thus, terpinolene can be considered as a potential drug in the management of pain associated with diabetic peripheral neuropathy.

Ulcerative colitis (UC) is a colon inflammatory illness that causes significant harm to the colon tissues. Nelumbo nucifera G. has been used for hundreds of years in old-style medication for treating gastrointestinal issues like inflammation and ulcers. To explore the therapeutic effects of Nelumbo nucifera ethanolic extract (NNEE) on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced UC in a rat model and to reveal the probable mechanisms intricate in the anti-colitic activities of NNEE. Network pharmacology analysis of Nelumbo nucifera G. was performed to determine the targets and pathways. The UC was prompted by intrarectal treatment of TNBS and rats were given with the treatment of NNEE via oral gavage. Body weight, colon weight, length, disease activity index, spleen weight, thymus weight, Macroscopic, adhesion and histopathological scores, myeloperoxidase, nitric oxide, haematological, and antioxidant parameters were assessed in colon tissues. Inflammatory cytokines were also assessed in serum samples. A comprehensive set of 11 active components was determined to be essential to NNEE effectiveness against UC treatment based on network pharmacology. The study also identified 152 putative core therapeutic targets in addition to the top 5 targets, which are ESR1, NFKB1, SLC6A4, CREBBP, and HMGCR. After NNEE treatment, the body weights and thymus weight of rats significantly increased, as colon weight, spleen weight, disease activity index score and histological score. The haematological parameters were significantly restored such as an increase in haemoglobin, red blood cells, platelet count and a reduction in white blood cell count. However, nitric oxide and myeloperoxidase were found to be decreased with the restoration of antioxidant markers and a reduction in inflammatory cytokines levels when matched to TNBS-treated rats. NNEE decreases colonic injury in the TNBS colitis model and alleviates inflammatory and oxidative events. It does this by boosting mucus production, decreasing leukocyte migration, lowering serum levels of inflammatory cytokines, and restoring antioxidant parameters, all of which suggest that NNEE could be used as a medicinal plant to treat UC.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00458-7.

Background: The growing incidence of cancer worldwide necessitates the development of novel, effective, and affordable antineoplastic drugs. Clinacanthus nutans, an ethnomedicinal plant known for its diverse pharmacological properties, has shown promising anticancer potential. This study investigates the anticancer, anti-inflammatory, and antioxidant activities of a fraction isolated from Clinacanthus nutans leaves.

Results: Quantification of the total phenolic content of CNM.CF5.5 revealed a substantial presence of phenolic compounds. Antioxidant potential, assessed through DPPH, FRAP, and ABTS assays, demonstrated a clear dose-dependent increase in activity. The BSA denaturation assay further indicated marked anti-inflammatory effects, comparable to those of the diclofenac sodium standard. Cytotoxic evaluation by MTT assay confirmed potent growth inhibition of MCF-7 and A549 cells, with IC₅₀ values of 61.67 µg/mL and 81.62 µg/mL, respectively. HR-LCMS profiling of CNM.CF5.5 identified a diverse array of phytochemicals. Subsequent molecular docking studies, performed using the Maestro interface of the Schrödinger Suite, revealed favorable binding interactions between ligands from the fraction and cancer-associated proteins. Notably, vitexin and isovitexin exhibited strong interactions with CDK1, CDK2, and human NAD[P]H-quinone oxidoreductase, supporting their potential role as key anticancer constituents of the fraction.

Conclusion: These findings support the potential of CNM.CF 5.5 bioactives as suitable agents in cancer therapy.

Marine algae are known for producing a wide variety of bioactive secondary metabolites. The present study investigated both in vitro and in silico approaches to evaluate the antioxidant, antibacterial, and anticancer properties of brown seaweed Sargassum cristaefolium, aim of assessing its biological activities. Preliminary phytochemical analysis revealed the presence of eight phytochemical constituents exhibiting notable biological properties. The seaweed extract was characterized using FT-IR and GC-MS, which identified various functional groups, including alkanes and anhydrides as well as bioactive compounds. Among these, phytol (3.66%) was the major bioactive compound in the ethanolic extract. The extract also demonstrated strong antioxidant activity, with an IC₅₀ value of less than 127.96 µg/mL. Furthermore, ethanolic extract exhibited significant antibacterial activity against Mycobacterium smegmatis (15.3 ± 0.50 mm) and anticancer efficiency against the A549 lung cancer cell line with an IC₅₀ value of 222 µg/mL. Computational analysis identified key compounds from S. cristaefolium, which showed strong binding affinities towards specific proteins such as DNA gyrase, human peroxiredoxin 6, and epidermal growth factor receptor (EGFR), supporting their potential as antioxidant, anticancer, and antibacterial agents for novel drug development.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00465-8.

Tuberculosis (TB) is a significant global public health challenge. Targeting enoyl-acyl carrier protein (ACP) reductase (InhA), an enzyme involved in mycolic acid biosynthesis, is a promising path to discovering an effective treatment for tuberculosis. This study assessed the inhibitory potential of bioactive compounds from four medicinal plants (Garcinia kola, Moringa oleifera, Newbouldia laevis, and Ocimum gratissimum) and control drugs (Isoniazid and Ethionamide) against InhA. Molecular docking and computational tools were used to evaluate the binding affinities and interactions with InhA's active site. Drug-likeness, binding affinities, bioactivity, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) attributes were determined using online tools. Ten out of twenty-three bioactive compounds studied were screened out due to violating Lipinski's, Ghose's, Veber's, Egan's, or Muegge's rules. The remaining thirteen compounds showed stronger binding affinities with InhA than the control drugs. The binding energy of the bioactive compounds ranged from - 8.0 to - 9.5 kcal/mol, while those of Isoniazid and Ethionamide were 6.1 kcal/mol and - 6.0 kcal/mol, respectively. The compounds also exhibited hydrogen bonds, hydrophobic, and π stacking interactions with the protein residues. Molecular dynamic simulations confirmed that 5,7-dihydroxydehydroiso-α-lapachone had a compact and more stable complex with InhA than the hit ligands with high binding energies. The ADMET property of each hit ligand predicted its ability to effectively reach and remain at the target protein to exert its therapeutic influence. The study shows that the screened bioactive compounds, especially 5,7-dihydroxydehydroiso-α-lapachone, exhibit drug-like properties capable of inhibiting InhA, hence, could serve as a novel anti-tuberculosis drug.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00472-9.

Background: Neurodegenerative diseases, marked by progressive brain cell damage, pose a major health challenge due to complex causes like oxidative stress and inflammation. Tamarindus indica, a plant rich in bioactive flavonoids and terpenoids, is underexplored for its neuroprotective potential against chemical-induced neuronal injury.

Methods: We used computational tools (network pharmacology, molecular docking, and molecular dynamics simulations) to investigate how Tamarindus indica fruit pulp ethanol extract's bioactive compounds might protect against neurodegeneration. Additionally, we tested the extract in a rat model of acrylonitrile-induced neuronal damage. Seventy male albino rats were divided into seven groups, receiving either acrylonitrile alone, Tamarindus indica extract (200 or 400 mg/kg) before or after acrylonitrile, or a standard drug (donepezil). Over the course of 28 days, we measured oxidative stress, inflammation, and brain enzyme activity.

Results: Network pharmacology, molecular docking, and molecular dynamics simulations mapped and validated interactions between T. indica bioactives and neurodegenerative pathway targets, revealing strong binding affinities and stability of T. indica bioactives, particularly apigenin, to key neuroprotective targets. In vivo, the extract significantly enhanced antioxidant enzyme activity, reduced lipid peroxidation, downregulated pro-inflammatory cytokines, and inhibited acetylcholinesterase, a key enzyme in neurodegeneration.

Conclusions: These findings position T. indica extract as a promising multi-targeted therapy for neurodegenerative disorders, leveraging antioxidant and anti-inflammatory mechanisms. Further preclinical and clinical studies are needed to translate these insights into novel treatments, bridging traditional phytotherapy with modern pharmacology.

West Nile Virus (WNV), a globally distributed mosquito-borne flavivirus, poses a significant public health threat due to its potential to cause severe neurological complications and the absence of licensed vaccines or specific antiviral treatments. In this study, we applied an integrated artificial intelligence, structural, and immunoinformatics-driven approach to design a multi-epitope subunit vaccine (MESV) targeting the non-structural proteins NS1 and NS4B, which play key roles in viral replication and immune evasion. B-cell, cytotoxic T lymphocyte (CTL), and helper T lymphocyte (HTL) epitopes were computationally predicted and screened for high antigenicity, non-allergenicity, and non-toxicity. Selected epitopes were assembled into a 307-amino-acid construct incorporating the 50S ribosomal protein L7/L12 and RS09 as adjuvants, along with a PADRE sequence to enhance T-helper responses. Structural modeling, physicochemical analysis, and mRNA structure prediction confirmed stability, solubility, and immunogenic potential. Molecular docking and 100-ns molecular dynamics simulations demonstrated strong, sustained interactions with TLR3 and TLR4, with principal component analysis supporting conformational stability. Immune simulations predicted robust humoral and cellular responses, including elevated IgM, IgG1, IgG2, cytokine production, and memory formation. Population coverage analysis revealed broad HLA representation, particularly in Europe (99.55%). Codon optimization and in silico cloning confirmed suitability for E. coli expression. Collectively, these AI-assisted computational insights highlight the MESV as a promising WNV vaccine candidate and provide a rational framework for future experimental evaluation.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00459-6.

Areca catechu nut exhibits potential antidiabetic properties due to its bioactive compounds, including alkaloids, flavonoids, and phenolic compounds, which enhance insulin sensitivity and glucose uptake. However, the specific compounds responsible and their underlying mechanisms remain undefined. This study employed an integrated computational and experimental approach to elucidate the antidiabetic action of Areca catechu. Phytochemicals were retrieved from Dr. Duke's and IMPPAT databases, and molecular targets were predicted using SwissTargetPrediction, SEA Search Server, and Binding Database. Disease-associated targets were obtained from DisGeNet, GeneCards, and MalaCards databases. Network pharmacology analysis identified carbonic anhydrase II (CA-II) as a key therapeutic target. Molecular docking using BIOVIA Discovery Studio revealed -CDOCKER Interaction Energy of chrysophanic acid (64.20 kcal/mol), isorhamnetin (62.52 kcal/mol), quercetin (54.54 kcal/mol), and ferulic acid (52.13 kcal/mol) had stronger binding affinities for CA-II than the reference inhibitor, acetazolamide (36.80 kcal/mol). These compounds were quantified using LC-MS/MS in nut extract, and their CA-II inhibitory activity was assessed using an in vitro assay. Chrysophanic acid exhibited the highest inhibitory activity (IC₅₀ = 0.3125 ± 0.03 µM), demonstrating a potency 17.9-fold greater than the reference drug, acetazolamide. Additionally, 100ns molecular dynamics simulations confirmed the stability of chrysophanic acid-CA-II interactions. Taken together, these results suggest that CA-II inhibition is a potential mechanism for the antidiabetic effects of Areca catechu. They also identify key lead compounds for future development as antidiabetic agents.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00464-9.