Targeting necroptosis in MCF-7 breast cancer cells: In Silico insights into 8,12-dimethoxysanguinarine from Eomecon Chionantha through molecular docking, dynamics, DFT, and MEP studies

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(1), P. e0313094 - e0313094

Published: Jan. 7, 2025

Breast cancer remains a significant challenge in oncology, highlighting the need for alternative therapeutic strategies that target necroptosis to overcome resistance conventional therapies. Recent investigations into natural compounds have identified 8,12-dimethoxysanguinarine (SG-A) from Eomecon chionantha as potential inducer. This study presents first computational exploration of SG-A interactions with key necroptotic proteins—RIPK1, RIPK3, and MLKL—through molecular docking, dynamics (MD), density functional theory (DFT), electrostatic (MEP) analyses. Molecular docking revealed exhibited stronger affinity MLKL (-9.40 kcal/mol) compared co-crystallized ligand (-6.29 kcal/mol), while its RIPK1 (-6.37 RIPK3 (-7.01 was lower. MD simulations further demonstrated stability within site, RMSD values stabilizing between 1.4 3.3 Å over 300 ns, indicating consistent interaction pattern. RMSF analysis indicated preservation protein backbone flexibility, average fluctuations under 1.7 Å. The radius gyration (Rg) results value ~15.3 across systems, confirming role maintaining integrity. Notably, maintains two critical H-bonds active site MLKL, reinforcing interaction. Principal component (PCA) reduction MLKL’s conformational space upon binding, implying enhanced stabilization. Dynamic cross-correlation map (DCCM) induced highly correlated motions, reducing internal ligand. MM-PBSA binding efficacy SG-A, free energy -31.03 ± 0.16 kcal/mol against surpassing control (23.96 0.11 kcal/mol). In addition, individual residue contribution highlighted interactions, ARG149 showing (-176.24 MLKL-SG-A complex. DFT MEP studies corroborated these findings, revealing electronic structure is conducive stable characterized by narrow band gap (~0.16 units) distinct favourable induction. conclusion, has emerged compelling inducer breast therapy, warranting experimental validation fully realize potential.

Language: Английский

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Theranostic Potential of Copper-64 ATSM Targeting MTHFD2: An In Silico Perspective on Hypoxia-Selective Imaging and Therapy

Cell Biochemistry and Biophysics, Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

Language: Английский

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Exploring Radioiodinated Anastrozole and Epirubicin as AKT1-Targeted Radiopharmaceuticals in Breast Cancer: In Silico Analysis and Potential Therapeutic Effect with Functional Nuclear Imagining Implications

Molecules, Journal Year: 2024, Volume and Issue: 29(17), P. 4203 - 4203

Published: Sept. 4, 2024

This study evaluates radio-iodinated anastrozole ([125I]anastrozole) and epirubicin ([125I]epirubicin) for AKT1-targeted breast cancer therapy, utilizing radiopharmaceutical therapy (RPT) personalized treatment. Through molecular docking dynamics simulations (200 ns), it investigates these compounds’ binding affinities mechanisms to the AKT1 enzyme, compared co-crystallized ligand, a known inhibitor. Molecular results show that [125I]epirubicin has highest ΔGbind (−11.84 kcal/mol), indicating superior affinity [125I] (−10.68 kcal/mol) ligand (−9.53 kcal/mol). (MD) confirmed stable interaction with [125I]anastrozole reaching stability after approximately 68 ns an average RMSD of around 2.2 Å, while stabilized at 2.69 Å 87 ns. RMSF analysis showed no significant shifts in residues or segments, consistent patterns differences less than 2 maintaining enzyme stability. The complex maintained four H-bonds, strong interactions, consistently formed three H-bonds. Rg values both complexes were ~16.8 ± 0.1 changes enzyme’s compactness, thus preserving structural integrity. These analyses reveal minimal perturbations, suggesting high potential inhibition. MM-PBSA calculations confirm compounds as inhibitors, exhibiting most favorable energy (−23.57 0.14 (−20.03 0.15 (−16.38 highlighting role electrostatic interactions stabilizing complex. computational shows may play promising roles especially its dynamic receptor interactions. findings, supported by scores energies, advocate their inhibitory capability against enzyme. Nevertheless, is crucial validate predictions through vitro vivo studies thoroughly evaluate therapeutic viability

Language: Английский

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Identification of natural compound inhibitors for substrate-binding site of MTHFD2 enzyme: Insights from structure-based drug design and biomolecular simulations

Chemical Physics Impact, Journal Year: 2024, Volume and Issue: unknown, P. 100809 - 100809

Published: Dec. 1, 2024

Language: Английский

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