In silico pharmacology最新文献

Zika virus (ZIKV), a mosquito-borne flavivirus, has emerged as a global health concern due to its association with congenital microcephaly and neurological disorders. The non-structural protein NS4A plays a pivotal role in viral replication and immune evasion by antagonizing the mitochondrial antiviral signaling protein (MAVS). In this study, we evaluated four NS4A mutations (L48M, K42E, F4L, and E8D). Only F4L and E8D showed destabilizing effects and were selected for further analysis. We used molecular docking, 300 ns molecular dynamics simulations, and binding free energy calculations to assess their effects on NS4A-MAVS binding. Stability investigations root means square deviation (RMSD) root mean square fluctuation (RMSF) and radius of gyration (Rg) revealed that both mutations changed the conformational dynamics of NS4A-MAVS complexes, with F4L displaying transitory fluctuations and E8D exhibiting long-term structural flexibility. Hydrogen bond research revealed that both mutants had stronger interaction networks with MAVS compared to the natural type. MM/PBSA computations showed that F4L and E8D had reduce binding affinities, with ΔG values of - 54.05 kcal/mol and - 56.25 kcal/mol, respectively, compared to - 61.73 kcal/mol in the wild type. The stronger electrostatic contributions observed in the E8D complex highlight its potential to further disrupt MAVS-mediated interferon induction. Collectively, these results suggest that the F4L and particularly E8D mutations enhance the immune-evasive capacity of ZIKV by stabilizing NS4A-MAVS interactions, offering insights into viral pathogenesis and providing a computational basis for therapeutic targeting of NS4A.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00540-0.

The bamboo plant Chamaedorea seifrizii is mostly used for its aesthetic qualities and air-purifying capabilities. The purpose of this study was to chemically profile and assesses the in-vitro anti-cancer properties of acetone extracts of Chamaedorea seifrizii's auxiliary inflorescence and fruits. Molecular dynamics modelling in conjunction with in silico research was also used to determine how certain components interacted with anticancer responses. The bioactive substances in fruit extracts and accessory inflorescence were identified with a gas chromatography-flame ionization detector (GC-FID). HeLa cancer cell line was used in anticancer investigations employing the MTT assay. GC-FID revealed phenethyl cinnamate (45%) and nezukol (10%) as major compounds in the auxiliary inflorescence and fruits extracts, respectively. Docking analysis revealed affirmative affinity of selected compounds with RelB receptors. With RelB receptor, docking score of phenethyl cinnamate and nezukol was - 8.3 and - 7.1 kJ/mol, respectively. The findings of the interaction studies indicated that the receptor-ligand complexes contain hydrogen bonding, alkyl bonding, and sigma interactions. The stability of best docked complexes (RelB-ligands) was further confirmed by post-MD analysis, as seen by the RMSD values. MM-PBSA analysis revealed best docked structures with binding free energy of 168 kJ mol^-1. Both bioactive compounds possess good pharmacokinetic properties as evidenced by ADMET/PASS study. Cytotoxicity studies further validated the in silico findings as the viability of HeLa cell lines reduced to 68% and 14% with Chamaedorea seifrizii's auxiliary inflorescence and fruits extracts, respectively. Chamaedorea seifrizii may be utilized to create new herbal cures for a variety of ailments, which might lead to the creation of innovative medications that have pharmacological and anticancer activities.

ABCG2, an ATP-binding cassette (ABC) transporter G2, also known as Breast Cancer Resistance Protein (BCRP), primarily found on the membrane of breast cancer cells, actively effluxes xenobiotics from cells, effectively lowering the concentration of drugs inside cells and contributing to the development of drug resistance. The present study aimed to identify potent ABCG2 inhibitors from the COCONUT database that may enhance the efficacy of anticancer drugs using computational techniques. Virtual screening of the complete COCONUT database resulted in 145 compounds with binding affinities lower than - 12.00 kcal/mol, indicating a stronger affinity than that of the reference inhibitor (febuxostat). Prime MMGBSA calculations further refined the selection, identifying the top 30 compounds with binding free energies ranging from - 65.02 to - 80.22 kcal/mol. These compounds not only conform to Lipinski's rule of five and other drug-like properties, but subsequent scaffold analysis has also identified that 12 of them possess a flavone backbone substructure. This substructure is recognized for its anticancer properties and its role as an inhibitor of ABC transporters. Binding pose metadynamics (BPMD) simulations over the top 30 ligands were used to further assess their stability. Molecules CNP0145817 (L1), CNP0114639 (L2) and CNP0288837 (L3) have demonstrated superior stability compared to the reference molecule Febuxostat (K1). Additionally, 100 ns molecular dynamics simulations were performed to explore the interaction dynamics, highlighting the key hydrophobic contacts and hydrogen bonds critical for binding stability. Important hydrophobic interactions, such as pi-pi, occur with residues such as PHE 432, PHE 439 as well as hydrogen bonds with residue ASN 436 of both chains A and B chain. The identified natural compounds exhibited strong binding affinities, stability, and favorable drug-like properties, rendering them promising candidates for overcoming ABCG2-mediated drug resistance and potentially aiding breast cancer treatment. These findings offer new avenues for drug development and improving therapeutic efficacy, although further in vitro analysis is required prior to clinical testing of the drug.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00521-3.

The current treatment scenario for antifungal drugs is limited and requires more research. Three structural classes of drugs, namely polyenes, azoles, and echinocandins, are widely used in the treatment of human fungal infections caused by Candida species. Although there is an increase in the number of antifungals, the number of issues (resistance, toxicity, and adverse effects) with these drugs has also increased. To address such issues, we have previously reported that a natural compound, Sodium lignosulfonate (LIG), that exhibits in vitro susceptibility against major Candida species, making it a potent lead. However, the pharmacological acceptance of LIG as a lead molecule is dependent on a plethora of pharmacological properties. Therefore, we have deciphered some important pharmacological properties of LIG, like aqueous solubility, lipophilicity index, pKa, bioavailability, plasma protein binding behavior, etc., in this study. Further, we have noticed a significant reduction in the growth and development of the human fungal pathogen Candida albicans cells after 24 h of treatment with LIG. Overall results strongly indicated LIG as a bioactive molecule, and the pharmacological significance of LIG could be selected for further in vivo and clinical studies to make it an effective antifungal biotherapeutic molecule in the future.

Neglected tropical diseases (NTDs) are prevalent in developing countries, leading to significant morbidity and mortality. Despite affecting millions, these diseases receive limited attention from pharmaceutical companies due to their low profitability, resulting in minimal research on novel therapies. Schistosomiasis, caused by Schistosoma mansoni, is a particularly concerning NTD that infects over 250 million people worldwide. While the current treatment with praziquantel is cost-effective, emerging drug resistance underscores the urgency for new therapeutic agents. Natural products, particularly medicinal plants like Copaifera oblongifolia, offer a promising source for novel drug discovery. Therefore, this study investigates the chemical composition of hexane fraction C. oblongifolia leaves. and its in vitro and in silico schistosomicidal activity. Through a series of extractions and gas chromatography-mass spectrometry (GC-MS) analysis, the n-hexane fraction contained triterpenes and steroids, which exhibited schistosomicidal activity against adult S. mansoni worms. The n-hexane fraction, particularly rich in these bioactive compounds, demonstrated 100% mortality at 100 µg/mL. In silico molecular docking was performed against S. mansoni thioredoxin glutathione reductase (TGR; PDB ID: 2XBI), a validated redox-regulating enzyme target. Among the identified compounds, β-amyrin showed the strongest binding affinity (- 7.4 kcal/mol, Ki: 3.7 μM), followed by lupeol (- 7.2 kcal/mol, Ki: 5.25 μM), both outperforming the reference drug praziquantel (- 6.5 kcal/mol, Ki: 7.34 μM). These findings indicate that C. oblongifolia contains compounds with promising antischistosomal activity. Further isolation, characterization, and in vivo studies are needed to confirm their potential as natural drug leads.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00501-7.

Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival and plasticity. An in silico analysis was performed on missense variants of BDNF retrieved from dbSNP and UniProt, filtered by allele frequency and evaluated through a consensus of 13 predictive tools (PredictSNP1.0, iStable, and DynaMut2) to estimate their effects on protein stability and dynamics. Among the 25.241 reported variants, eight substitutions were prioritized as potentially deleterious, five of which were examined in greater detail due to their predicted impact on protein stability. High-confidence variants were structurally inspected using the AlphaFold model (AF-P23560-F1) to ensure reproducibility. These findings provide a set of candidate variants that may alter BDNF structural properties; however, experimental validation is required and will serve as a foundation for future investigations into their functional relevance and therapeutic implications in neurodegenerative diseases.

Tinospora cordifolia is a well-known Ayurvedic medicinal plant with reported immunomodulatory and anticancer properties, yet integrated studies linking its phytochemistry to biological and molecular mechanisms remain limited. In this study, the methanolic extract of T. cordifolia was evaluated for antioxidant and cytotoxic activities, alongside computational investigations of its key phytoconstituents. Spectroscopic analyses (FTIR and UV-Vis) confirmed the presence of functional groups such as amines, phenolics, and aromatic systems. The extract demonstrated notable antioxidant potential and exhibited significant cytotoxicity against Dalton's lymphoma ascites, Ehrlich Ascites Carcinoma, and MCF-7 breast cancer cell lines, with morphological changes suggestive of apoptosis or necrosis. Computational studies using density functional theory and molecular docking highlighted Tinocordiside as the most bioactive compound. Tinocordiside showed favorable frontier molecular orbital properties and strong binding affinity to the EGFR tyrosine kinase domain, forming multiple hydrogen bonds with critical residues and displaying a docking score comparable to Erlotinib. In contrast, despite its promising activity, Tinocordiside's bulky glycosidic structure and poor solubility may limit cellular permeability and bioavailability. This underscores the need for apoptosis marker studies in vitro, in vivo validation, and advanced formulation strategies such as amorphous solid dispersions, lipid-based nanoparticles, or cyclodextrin complexes to enhance its therapeutic potential. In summary, T. cordifolia methanolic extract exhibits potent antioxidant and anticancer activity, with Tinocordiside as a promising EGFR-targeting lead compound for further therapeutic exploration.

Alzheimer's Disease (AD) is a brain disorder with various neuropathological hallmarks and has become a major concern globally due to limited therapeutic options. Cholinergic dysfunction due to the depletion of acetylcholine (ACh) levels in the synapse caused by increased acetylcholinesterase (AChE) activity is one of the major factors that drives AD progression. AChE also accelerates amyloid beta (Aβ) formation and leads to amyloid plaque deposition in the brain. Production of Aβ from amyloid precursor protein (APP) with sequential cleavage by β-secretase (BACE1) and γ-secretase causes severe brain damage due to plaque toxicity. Neurofibrillary tangles (NFTs), a neuronal catastrophe resulting from hyperphosphorylation of tau protein due to upregulation of glycogen synthase kinase 3 beta (GSK3β) and downregulation of Wnt signaling because of Dickkopf-1 and low density lipoprotein receptor-related protein 6 (DKK1-LRP6) interaction, are a major pathogenic event in AD. Recent research has increasingly focused on targeting amyloidopathy, tauopathy, and cholinergic pathways as therapeutic strategies for mitigating AD pathology. Coptisine, a bioactive alkaloid having enormous pharmacological properties, including neuroprotective action, is considered in our in-silico investigation. Collective inhibition of key targets in AD pathogenesis, like AChE, β-secretase (BACE1), γ-secretase, GSK3β, and DKK1-LRP6 interaction, could be a positive approach in the arsenal of Alzheimer's treatment. In this article, we report that coptisine can inhibit these five major targets as evident from our molecular docking study, and propose it as a potential multi-target drug to play a key role in halting AD pathology. Further, comparative analysis based on predicted values of cheminformatics and pharmacokinetic profiling of coptisine and known inhibitors increases its possibility to ameliorate AD. However, robust research, including a preclinical and clinical study on coptisine for its safety and efficacy assessment against AD pathology, is warranted for its validation as an anti-AD drug.

Oropouche fever, caused by the Oropouche virus (OROV), presents an emerging health threat, particularly in tropical regions, due to its severe impact on human health and the lack of available vaccines. Since its initial identification in Trinidad and Tobago in 1955, OROV has led to multiple outbreaks across South America. This study aims to develop a multi-epitope-based mRNA vaccine construct for OROV using in-silico methodologies. We identified potential T-cell, B-cell, and helper T-cell epitopes from selected OROV proteins, prioritizing those that are non-allergenic, non-toxic, antigenic, and capable of inducing both humoral and cell-mediated immune responses across diverse populations. Molecular docking was employed to assess interactions between selected epitopes and MHC alleles. Twelve epitopes, a tPA signal peptide, the RpfE adjuvant, and specific linkers were assembled into the mRNA vaccine construct. Immune simulations indicated favorable immunogenicity in humans. Codon optimization and in silico cloning demonstrated efficient mRNA translation in human cells and successful vector integration. Further molecular docking and dynamics simulations with TLR-4 and TLR-3 confirmed the stability and interaction of the vaccine construct with immune receptors. These findings suggest that the proposed vaccine could be a promising candidate for OROV prevention, pending further in vitro and in vivo validation.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00470-x.