In silico pharmacology最新文献

Utilizing the network pharmacology approach to investigate the anticervical cancer activity of apigenin, daidzein, and isokaempferide of Glycyrrhiza glabra Linn. methanolic extract. The systematic pharmacological analysis platform of Swiss Target and the HRMS/MS studies provided information about the active ingredients of G. glabra Linn and potential targets in the cervical cancer (CC). We mapped the CC and its targets using disease databases like GeneCards and DisGeNet, which are used for mining gene targets associated with CC, and screened the core targets. We built the protein-protein interaction network (PPI) using the Cytoscape and STRING databases. The ShinyGo web tool was used to conduct pathway enrichment analysis of overlapping targets for gene ontology (GO) and Kyoto Encyclopaedia of Gene and Genome (KEGG), cellular components, molecular functions, and their biological processes. The three constituents, apigenin, daidzein, and isokaempferide understand the primary therapeutic targets and roles of herbal decoctions in clinical settings, which correspond to a stronger binding affinity with the target of CC. The findings of our network pharmacology investigation made it clear that apigenin, daidzein, and isokaempferide of G. glabra Linn. methanolic extract may be used in anti-cervical cancer drug development.

Nipah virus (NiV) remains a lethal zoonotic pathogen with two major clades: NiV-Malaysia (NiV-M) and NiV-Bangladesh (NiV-B), representing a persistent global threat. While research has largely focused on NiV-M, NiV-B shows distinct pathogenicity, including higher mortality and increased human transmission. Molecular interactions, especially involving NiV-B attachment glycoprotein binding to host receptors, remain underexplored, prompting this study's focus. Thus, this study presents an in silico investigation of NiV-B attachment glycoprotein (AGP) mutations and their impact on binding to human ephrin receptors EFNB2 and EFNB3, key mediators of viral entry. Nineteen mutations in the NiV-B AGP globular head region were modelled to generate a mutant structure (AGP_MT), which was subjected to docking using HADDOCK, molecular dynamics simulations, and MM/PBSA binding free energy calculations. Compared to the wild-type AGP, the mutant showed stronger and more stable binding to both receptors. Principal component analysis and free energy landscape profiling indicated that these mutations modulate the dynamic flexibility and conformational stability of the receptor complexes, potentially contributing to enhanced viral infectiousness. Our computational characterization elucidates molecular mechanisms underlying NiV-B receptor specificity and offers critical structural insights. These findings lay the groundwork for in silico screening of small molecules or peptides targeting the AGP-EFNB interface, providing promising leads for therapeutic development against NiV infections. This study exemplifies how advanced computational pharmacology methods can bridge molecular virology and drug discovery, accelerating efforts to combat emerging viral threats.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00535-x.

Rheumatoid arthritis (RA) is a prevalent chronic inflammatory condition. The cause of RA involves a complex system of cytokines and cells that stimulate the growth of synovial cells and cause damage to cartilage and bone. TNF-α is a pivotal pro-inflammatory cytokine in the etiology of RA, whereas glucocorticoids (GCs) are powerful immunomodulator that frequently employed to mitigate of inflammation. Alongside TNF-α, other cytokines including IL-17 and IL-18, as well as inflammatory mediators and enzymes such as COX-2, MMP-7, MMP-9, and MMP-13, significantly contribute to joint inflammation and tissue degradation in RA. Dexamethasone sodium phosphate (DSP) has a significant therapy effect on RA by diminish the regulation of cytokines and inhibiting the function of leukocytes, and fibroblasts. In present study, novel pharmacophore features of DSP has been determined via computational assessment which provide new approaches for management of RA. The docking score values on different receptors for anti-arthritis activity, it is observed that DSP, namely, IL-18, COX-2, MMP-9 and Mineralocorticoid showed the best docking results. It has been found that DSP has some new targeting arability towards Spleen tyrosine kinase (Syk), Interferon (IFN)-γ, Nicotinamide phosphoribosyl transferase (NAMPT) or Visfatin, NF-κB receptors which are responsible for RA regulation. Further, anti-inflammatory assay suggests its anti-arthritic activity and MTT assay divulge its toxicity towards pro-inflammatory macrophages. In order to determine the effectiveness of DSP in treatment of RA, the DSP has been administered to complete Freund's adjuvant (CFA) developed rat. The anti-arthritic impact was evaluated by measuring the arthritic index; hind paw volume, X-ray imaging, and histopathology of ankle joints in arthritic rats.

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Alzheimer's disease (AD) is a multifaceted neurological condition noticeable by neurodegeneration, progressive cognitive impairment, and memory loss. Several interconnected pathological pathways work in harmony to present clinical AD. Currently available anti-AD therapeutics are capable of targeting a few pathways while others remain unchecked, leading to AD progression despite continuous therapy. The current study aimed to discover the potential of Aegle marmelos (AM) bioactives against AD and identify key pathological targets using Network Pharmacology (NP) and Molecular Docking approach. 14 bioactive compounds from AM were identified to have potential anti-AD activity based on favorable pharmacokinetic, safety profiles, NP predictions, and molecular docking validations. Ammijin, O-isopentenylhalfordinol, clionasterol, and fenretinide demonstrated notable binding affinity toward key AD-associated targets, show stronger affinity internal standards used in the study (donepezil and rivastigmine). Protein-protein interaction (PPI) analysis, Gene Ontology (GO), and KEGG pathway enrichment analysis showed that these compounds may influence critical pathological pathways involved in AD progression. The findings provide insight into the multi-targeted potential of AM bioactives against AD. Our results not only provided experimental justification for the ethnomedicinal use of AM as a neuroprotectant but also revealed key bioactives and targeted pathways that could be exploited for developing new plant-based therapeutic approaches for AD management. Further in-vitro and in-vivo investigations are necessary to validate these results and explore their practical applications.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00559-x.

Alzheimer's disease (AD) is a neurodegenerative condition most often occurring in aged individuals and displaying symptoms of memory impairment, cognitive decline, and behavioral disturbances. With a significant reduction in acetylcholine levels, the disruption of the cholinergic system is an essential part of AD pathogenesis. By increasing the availability of acetylcholine and thus enhancing cholinergic transmission, acetylcholinesterase inhibitors (AChEIs) like galantamine, donepezil, and rivastigmine are employed to alleviate symptoms. In this study, the prospect of phytoconstituents of Senecio species collected from various literature (GC-MS and LC-MS data) as inhibitors of acetylcholinesterase (AchE) is investigated. A total of 250 compounds were screened for ADMET using SwissADME database. Out of these 42 were eligible for the docking study. The docking results revealed that 2 compounds (Piperitol [4EY7-PIP]) and (4R)-4-hydroxy-4,5,5-trimethyl-3-[(E)-3-oxobut-1-enyl]cyclohex-2-en-1-one [xxx]) showed stronger binding to the AchE receptor than the standard drug, donepezil. Further, the compounds were subjected to Molecular dynamics simulations for 100ns. The results revealed that these molecules significantly stabilized proteins in different parameters, such as RMSD, RMSF, Rg, SASA, and MM-PBSA. The inspection of solvent interaction, structural compactness, and molecular flexibility underlined the desirable interaction and dynamic stability of 4EY7-PIP. Steered Molecular Dynamics (SMD) uses externally applied forces to probe molecular interactions, conformational changes, and energy landscapes beyond the reach of conventional MD. Based on these findings, Senecio species most prominent phytoconstituent can be employed as a therapeutic agent against Alzheimer's disease, but more experimental studies are required to establish its value and therapeutic benefits.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00556-0.

Drug-resistant Plasmodium falciparum has been on the rise, mainly due to point mutations in the pfDHFR or dihydrofolate reductase gene. This has heightened urgency to discover and develop new antimalarial drugs. This research utilized Pharmacophore Modeling, Virtual Screening, Molecular Docking and Molecular Dynamics Simulation techniques to identify potential pfDHFR inhibitors from virtual databases. Ligand-based pharmacophore hypothesis (H1) (r = 0.949, r² = 0.883) was formulated using a training set of 28 compounds that demonstrated pfDHFR inhibitory activity across four orders of magnitude. Additionally, a Structure-based Pharmacophore Hypothesis (P1) was derived from the ligand-binding site in the pfDHFR protein. The thoroughly validated hypotheses (H1 and P1) were then employed as 3D queries to screen compounds from the chemical database. These compounds were initially screened for drug-likeness and ADME/Tox properties before undergoing pharmacophore mapping. Pharmacophore mapping and docking analyses, followed by 200 ns molecular dynamics simulations using a mutant pfDHFR model, identified three promising lead candidates from the TCM database. The top compound, ZINC70454408, exhibited the highest H Bond energy of -14.204 kcal/mol and a predicted Ki of 0.04 µM, maintaining structural stability with an average RMSD of 2.1 Å throughout the simulation. Two additional compounds, ZINC04096650 and ZINC85631105, also exhibited strong binding energies (- 122.64 and - 118.92 kcal/mol, respectively) and low predicted Ki values (< 0.1 µM), with stable RMSD values ranging between 2.0 and 2.4 Å. These findings underscore ZINC70454408 as the most promising natural product-based pfDHFR inhibitor candidate and provide a compelling rationale for future experimental validation.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00533-z.

Rheumatoid arthritis (RA) is a systemic inflammatory condition that can lead to increased death rates, severe disability, and destructive joint damage. The prevalence of RA is the most frequent of all inflammatory diseases and is reported to affect 0.1-2.0% of the population worldwide. The incidence and disability-adjusted life years rates of RA in India have shown an increasing trend from 1990 to 2021. In the current investigation, a pharmacoinformatics approach was used to explore the potential synthetic derivative compounds of curcumin against unexplored hub genes associated with the therapeutics of RA in the Indian population. Such investigations could not only cut short the in-vitro and in-vivo experimental approaches. Herein, a GWAS of RA was conducted in a genetically distinct Indian population. CD4, STAT4, and CCR6 genes were identified and reconfirmed by a few previously reported GWAS findings, which revealed CCR6 as one of the key targets associated with RA. Lipinski's rule was used to determine the adsorption, distribution, metabolism, and excretion of ligands for drug suitability, and acute toxicity was also predicted. However, further docking analysis was carried out for curcumin and its nine derivatives against CCR6, STAT4, and CD4 human proteins compared with standards, i.e., Methotrexate and Hydroxychloroquine. Based on molecular docking, toxicity, and pharmacokinetics, the MD simulation study was observed for CCR6, STAT4, and CD4 with Methotrexate complex, Hydroxychloroquine complex, and pentagamavuton complex, respectively. This study revealed pentagamavuton as an active therapeutic that majorly inhibits the activity of the pivotal receptor CCR6, STAT4, and CD4 in humans.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00547-7.

Kalanchoe blossfeldiana, a medicinal succulent known for rich phytochemical diversity, hasn't been extensively explored for lipid-lowering potential. Given growing burden of hyperlipidemia and limitations of current therapies, novel natural alternatives with multi-target synergistic mechanisms are of increasing interest. This study aimed to investigate antihyperlipidemic activity of K. blossfeldiana leaf extracts and its bioactive compounds through multidisciplinary approach. Sequential extractions were performed using solvents of increasing polarity. Phytochemical estimation revealed that ethanolic cold extract obtained via ultrasonic-assisted cold extraction exhibited highest phenolic (102.46 ± 2.05 µg/mL) and flavonoid (86.88 ± 1.29 µg/mL) content, LC-MS/MS-QQQ analysis identified 61 phytocompounds, including kaempferol-3-O-rutinoside, kaempferol-3-O-glucuronide, quercetin-3,4'-di-O-glucoside, quercetin-3-O-rutinoside, and apigenin-7-O-glucoside. Ethanolic cold extract showed potent pancreatic lipase inhibition via fluorometric assay (IC₅₀ = 23.33 µg/mL) comparable to standard orlistat and significantly improved lipid profiles in cholesterol-fed female albino rats, reducing cholesterol, triglycerides, LDL-C, and VLDL-C while increasing HDL-C (P < 0.005) comparable to standard atorvastatin. Molecular docking revealed strong binding affinities, particularly for quercetin-3-O-rutinoside against HMG-CoA reductase (- 9.023 kcal/mol) and quercetin-3,4'-di-O-glucoside against pancreatic lipase-colipase (- 9.139 kcal/mol). Molecular Dynamic simulations over 100 ns confirmed stability of these complexes with minimal RMSD and RMSF fluctuations. In silico ADMET profiling indicated favorable pharmacokinetic and toxicity profiles for both compounds (LD₅₀ 5000 mg/kg). Multidisciplinary evidence supports the ethanolic cold extract of K.blossfeldiana as promising antihyperlipidemic agent. Quercetin-based derivatives were identified as key bioactives, meriting further investigation for isolation and development as lead compounds. Further pharmacokinetic, toxicity, and efficacy studies are necessary for clinical translation.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00560-4.

Alternaria alternata is a common airborne fungus that can be found in both indoor and outdoor environments. It is a major allergen linked to respiratory diseases such as allergic rhinitis and asthma. It may also infect the skin, nails, or eyes. In addition, uncharacterized or hypothetical proteins are present but have not yet been identified or associated with specific protein sequences. Domains of undetermined activity refer to molecules with known, experimentally determined activity. Yet, the exact role or structural features of these proteins have not been identified. Many proteins encoded in A. alternata genome remain uncharacterized, including the hypothetical protein XP_018378625.1 containing the SRC1lrK2f domain, whose function is unknown. This research employed a comprehensive in-silico approach to predict its physicochemical features, structural properties, subcellular localization, and protein-protein interactions and 3D structure. The protein was found to be hydrophilic, with an instability index of 46.62 and isoelectric point value of 6.41 which indicates acidic nature. The in-silico analysis indicated that the protein is soluble, with its secondary structure mainly composed of a random coil suggesting structural flexibility. The analysis showed that the protein contains a cytoplasmic domain. Moreover, the protein-protein interactions were examined using STRING software, which showed that the SRC1lrK2f protein has a strong interaction with exodeoxyribonuclease 1, implying a possible role in DNA repair or genome maintenance. These findings provide the first functional insights into the SRC1lrK2f domain in A. alternata and may support the future development of pharmaceutical strategies for managing Alternaria-induced allergic and infectious diseases by advancing our understanding of the biological role of the SRC1lrK2f domain.

Carbapenemes are most powerful antibiotics available for the treatment of bacterial infections. However, bacteria have evolved the enzyme carbapenemase, specifically the New Delhi metallo-β-lactamase (NDM-1), hydrolyses broad spectrum of β-lactam antibiotics, including carbapenems, the last line of defense against infections, thus raising a significant global health issue. Hence, NDM-1 is a promising drug target against antibiotic resistance. A structure-based in silico approach employed to identify potential inhibitors of NDM-1. Virtual screening of 13,526 antibacterial compounds yielded ten candidates with the most favorable binding affinities (- 9.50 to - 8.07 kcal/mol), outperforming the reference ligand 7UOX-Lig (- 5.81 kcal/mol). Molecular dynamics simulations confirmed the stable binding of compounds 11,871, 12,801, 13,206, and 12,498, further supported by favorable MM/GBSA binding free energy values and consistent interaction profiles. The favorable thermodynamic profiles suggest that these compounds are promising NDM-1 inhibitors. They serve as potential leads for further optimization and experimental validation in developing novel therapeutics against NDM-1-mediated antibiotic resistance. Further in vitro and biochemical studies are warranted to confirm their efficacy and specificity, emphasizing the critical role of NDM-1 as a key target in combating β-lactam resistance.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00534-y.