In silico pharmacology最新文献

Over one billion peoples are currently infected with a parasitic nematode, particularly in tropical regions. Helminthiasis is a medical condition characterized by an infection of parasitic worms in the human body. Calotropis gigantea Linn. Belongs to the Asclepiadaceae family, commonly known as "Gaint milkweed" or "Crown flower" and recognized as a traditional medicinal plant. In this study, anthelminthic potential of Calotropis gigantea phytoconstituents were determined. Nematode kinases EGFR, MEK1, and PLK1 have diverged from their vertebrate counterparts in their drug-binding pockets. The development of novel anthelmintics targets Kinases that hold potential as targets. This pipeline revealed three potential anthelmintic targets that include epidermal growth factor tyrosine kinase transmembrane receptor [EGFR], the Mitogen-activate protein kinase [MEK1], and polo-like kinase [PLK1]. The software used in the in silico study investigation is the pyRx virtual screening tool, Biovia Discovery Studio, mol-inspiration, and RCSB [Protein Data Bank (PDB)]. The various phytoconstituents of Calotropis gigantea were docked Stigmasterol, beta-sitosterol, Desmosterol, alpha-amyrin, asclepin, and others showed high binding energies in EGFR, MEK1, and PLK1 receptors. This investigational study research highlights the potential of phytoconstituents from Calotropis gigantea as anthelmintic activity.

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In recent years, there has been growing concern about infections caused by Candida albicans, which pose a significant threat to human health. This intensifies the concern that can be largely attributed to the increasing number of people with compromised immune systems and the emergence of drug-resistant strains. Natural molecules are considered to be good alternatives to synthetic antifungal agents. The present study explored the effectiveness of alpha-bisabolol as an antifungal agent and its mechanism of action against C. albicans ATCC90028. α-bisabolol effectively inhibited various pathogenic traits of C. albicans like, adhesion, yeast to hyphal switching, and development of biofilm at 1 mg/ml, 0.25 mg/ml, and 0.125 mg/ml concentration, respectively. In addition, α-bisabolol demonstrated inhibition of cell cycle propagation at the G1 phase. Ergosterol production in the C. albicans was suppressed by α-bisabolol treatment in a dose-dependent manner. The molecular docking study revealed α-bisabolol has a good binding energy of - 7.11 kcal/mol with 14-α-demethylase enzyme, which is crucial for ergosterol synthesis. Therefore, the cell membrane integrity may be affected by treatment with α-bisabolol. qRT-PCR studies proved that α-bisabolol treatment affects gene expression in C. albicans. In silico binding affinity was also analyzed for RAS1, TUP1 and CST20 in the signal transduction pathway and exhibited binding affinities for at - 7.7 kcal/mol, - 8.21 kcal/mol, and for - 5.79 kcal/mol respectively. In conclusion, α-bisabolol caused reduced biofilm, ergosterol synthesis along with altered gene expressions in C. albicans with no hemolysis. This study proposed α-bisabolol as an alternative antifungal agent.

Piperine, a natural alkaloid found in black pepper (Piper nigrum), has the chemical formula C₁₇H₁₉NO₃ and a molecular weight of 285.34 g/mol. This research investigated its effect on the mTOR protein, which plays a crucial role in cancer development, using molecular docking, dynamic simulations, MTT, and scratch wound assays on the HCT-116 colon cancer cell line. Molecular docking revealed that piperine exhibited a binding affinity of - 8.3 kcal/mol to the mTOR protein, which is significantly comparable to rapamycin's binding affinity of - 8.8 kcal/mol, a well-known mTOR inhibitor. This comparison highlights that piperine demonstrates a substantial ability to interact with the mTOR binding site, making it a potential candidate for further evaluation. Molecular dynamics simulation studies over 100 ns confirmed that piperine remains stable and firmly bound to the mTOR active site, binding in an ATP-competitive mode. MTT assay results revealed that piperine significantly reduced cancer cell viability, with IC50 values of 84.5 ± 0.5 µM at 24 h, 46.3 ± 0.26 µM at 48 h, and 19.73 ± 0.25 µM at 72 h, while the scratch wound assay confirmed its inhibition of cancer cell migration, suggesting potential to suppress metastasis. These findings indicate that piperine is a promising mTOR inhibitor with potential applications in cancer therapy, though further research is needed.

Prostate cancer (PrCa) is a serious health concern for the affected people and, there is an increasing demand for a viable therapy that can address the limitations of current treatments with minimal or no adverse effects. This study aims to evaluate phytocompounds extracts of Mangifera indica as a potential therapy development for prostate cancer. Herein, molecular docking, QSAR, molecular mechanics/generalized born surface area (MM/GBSA) estimation, ADME screening, and molecular dynamics (MD) simulation were performed using the Schrodinger suite to identify 17β-hydroxysteroid dehydrogenase antagonist from Mangifera indica. The results showed that fisetin (-11.669), riboflavin (-10.918), quercetin (-10.843), gallic acid 6-phenylhexyl ester (-10.817), cianidanol (-10.608), (-)-epicatechin (-10.603), ellagic acid (-10.522), Butin (-10.124) in kcal/mol were predicted to possess greater inhibitory activities against the protein target based on their high binding energies and remarkable stability compared to the standard drug, docetaxel (-7.374 kcal/mol). Fisetin (-718.37), and riboflavin (-722.37) also have better induce fit score than docetaxel (-714.02) in kcal/mol with better pharmacokinetics profile compared to the standard drug.MD simulation over 100 ns predicts that Fisetin forms stable interactions with vital residues at the catalytic site of the protein. The observations from this study predict fisetin as a putative antagonist of 17β-hydroxysteroid dehydrogenase and should be experimentally verified as a lead compound for prostate cancer therapy.

The Mpox DNA polymerase (DNA pol) plays a crucial role in the viral replication process, making it an ideal target for antiviral therapies. It facilitates the synthetic process of viral DNA, which is an integral stage in the life of a virus. The inhibition of the operation of Mpox DNA pol would interfere with the multiplication of the virus and help manage the disease. Peptides have emerged as a possible therapeutic alternative against viruses due to their distinct characteristics. Peptides have broad-spectrum antiviral activity, being effective against a variety of viruses. Using computational techniques, we attempted to explore the molecular details of the interaction between antiviral peptides and Mpox DNA pol. Two databases of antiviral peptides were screened in this study. This study used molecular docking, followed by molecular dynamics (MD) simulation and post-simulation binding energy predictions. From the 19 selected peptides with activity against DNA polymerases, two peptides-DRAVPe01393 and DRAVPe01399-were identified as particularly promising candidates. These peptides exhibited stable interactions with Mpox DNA pol and demonstrated good cell penetration potential as evident from the MD simulation studies. Notably, the peptides DRAVPe01399 and DRAVPe01393 have a better binding affinity of - 60.86 kcal/mol and - 47.92 kcal/mol respectively than the control ligand Cidofovir diphosphate (- 10.79 kcal/mol). These findings could lead to the development of innovative antiviral treatments to prevent monkeypox, helping global efforts to battle this emerging infectious disease.

3-Mercaptopyruvate sulfurtransferase (3-MST) is an enzyme that plays integral roles in various biological processes. In the realm of Leishmania, the role of 3-MST is less explored. It is a critical player in maintaining oxidative homeostasis in Leishmania during stress for survival. This highlights the potential of Ld3-MST as an appealing drug target. However, recognising structural disparities becomes essential when a protein is present in the host and parasite. This study delves into the structural distinctions between Ld3-MST and Hs3-MST, providing valuable insights with direct implications for drug design. A standout feature of Ld3-MST is the elongated 70 amino acid C-terminal mainly contributing to a lid-like domain above the active site cavity, setting it apart from Hs3-MST. The RMSD analysis shows fluctuation due to the extended tail, while Rg and SASA confirm the open and solvent-accessible nature of Ld3-MST, especially in its active site, suggesting its ability to accommodate larger molecules. PC and FEL analysis reveals unique internal molecular dynamics of Ld3-MST, particularly in its active site. Docking studies demonstrate that Ld3-MST's active site can effectively accommodate molecules, highlighting its potential as a drug target. This comprehensive investigation lays the foundation for developing precise Ld3-MST inhibitors with promising therapeutic applications.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00340-6.

Doxorubicin, a potent anthracycline used in chemotherapy, is limited by dose-dependent cardiotoxicity, leading to irreversible heart damage and heart failure. Common symptoms include fatigue, dyspnea, lower limb edema, hypotension, tachycardia, and transient arrhythmias. Annona squamosa L. (AS), traditionally used in medicine, was investigated for its cardioprotective action against doxorubicin-induced cardiotoxicity through computational studies. Phytocompounds were identified using literature reviews, Dr. Duke's, IMPPAT, and PubChem databases. Targets associated with Doxorubicin induced cardiotoxicity were accessed from GeneCards, and protein-protein interactions were analyzed using the STRING database. Cytoscape was used for network visualization, revealing 18 bioactives targeting 67 proteins across 14 pathways. PIK3R1 emerged as a key target with the highest interaction count among 767 targets. Molecular docking showed that the PIK3R1-Rutin complex had the lowest binding energy (- 11.873 kcal/mol), and a 100 ns molecular dynamics (MD) simulation confirmed its stability. LC-MS analysis of the crude extract indicated the presence of bioactives. In vitro antioxidant activity of AS, assessed using the DPPH assay, showed significant radical scavenging activity, correlating with the high total phenol (TPC) and total flavonoid content (TFC) detected. This integrated approach highlights AS's potential in mitigating doxorubicin-induced cardiotoxicity.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00333-5.

Spinocerebellar Ataxia Type 1 (SCA1) is a progressive neurodegenerative disorder caused by the expansion and aggregation of polyglutamine (polyQ) in the Ataxin-1 (ATXN1) protein, leading to severe neuronal dysfunction. Currently, only symptomatic treatments are available, highlighting the requirement for disease-modifying therapies. This study employed a detailed in silico approach to identify potential neuroprotective natural compounds targeting the Ataxin-1 protein implicated in SCA1. The three-dimensional structure of Ataxin-1 was retrieved, validated, and optimized to achieve a stable structural model. Validation using a Ramachandran plot indicated that 77% of the residues were in favored regions, confirming the reliability of the protein structure. Active site residues were identified using CASTp, and receptor grids were generated for molecular docking studies. A library of 50 natural compounds was screened, among which 21 satisfied Lipinski's rule of five. Molecular docking using PyRx and AutoDock 4.2 identified Withanolide A as the top candidate, exhibiting the highest binding affinity (- 10.14 kcal/mol) and forming four hydrogen bonds with key active site residues. The top six ligands were further assessed for ADMET properties, with Withanolide A showing optimal drug-likeness, high gastrointestinal and blood-brain absorption, and non-toxic profiles. Molecular dynamics simulations over 200 ns demonstrated the stability of the Ataxin-1-Withanolide A complex, supported by RMSD, RMSF, RoG, and SASA analyses. PCA revealed reduced conformational flexibility, indicating enhanced structural stability of the ligand-bound complex. Additionally, MM-PBSA analysis confirmed that Van der Waals interactions were the primary stabilizing forces, complemented by electrostatic contributions. This integrated computational approach highlights the therapeutic potential of Withanolide A as a neuroprotective agent for SCA1, providing a base for future experimental validation and drug development.

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Aloe-emodin (AE) has drawn interest due to its potential activity against type II diabetes mellitus (T2DM). However, the mechanisms underlying its antidiabetic activity are not well explored. Using network pharmacology, molecular docking and molecular dynamics simulation studies, we investigated its molecular mechanisms in the management of T2DM. Potential target genes of AE were predicted using the Swiss Target Prediction (http://www.swisstargetprediction.ch/) database. The GeneCards, OMIM and DisGeNET databases were used to compile a comprehensive list of genes associated with T2DM. A compound-disease-target network was constructed, and protein-protein interaction networks were analysed to identify hub genes. Finally, molecular docking and interaction analysis between AE and the identified proteins were performed using AutoDock tools. Investigation of AE targets and genes associated with T2DM identified 32 overlapping genes. Gene ontology studies revealed that AE may exert its anti-diabetic effects by modulating glucose metabolism and enhancing cellular response to glucose. Furthermore, KEGG pathway analysis suggested that AE influences these processes by targeting pathways related to apoptosis, insulin resistance, and T2DM signaling. The core target proteins identified were TNF, ALB, TP53, PPARG, BCL2, CASP3, and EGFR. AE interaction with each of these proteins exhibited a binding energy of > - 5 kcal/mol, with TNF showing the lowest binding energy (- 7.75 kcal/mol). Molecular dynamics simulation further validated the molecular docking results with TNF and EGFR exhibiting a strong affinity for AE and forming stable interactions. AE exerts its antidiabetic activity through multiple mechanisms, with the most significant being the amelioration of pancreatic β-cell apoptosis by binding to and inhibiting the actions of TNFα. Further cellular and molecular studies are needed to validate these findings.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00337-1.