In silico identification of novel CDK4 inhibitors for retinoblastoma.

Chemical Physics Impact, Год журнала: 2024, Номер unknown, С. 100743 - 100743

Опубликована: Сен. 1, 2024

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Integrated Computational and Experimental Insights Into MEK1/2 Inhibitors: Structural Validation, Docking, ADMET, Molecular Dynamics, and Anticancer Evaluation

Chemistry & Biodiversity, Год журнала: 2025, Номер unknown

Опубликована: Март 5, 2025

This study explores the therapeutic potential of novel MEK1/2 inhibitors targeting MAPK pathway, emphasizing their critical role in cancer progression. An integrated computational approach, including molecular docking, pharmacophore modeling, dynamics simulations, and DFT analysis, was employed to evaluate binding affinity, stability, pharmacological properties FDA-approved experimental compounds. Structural validation MEK1 (PDB ID: 1S9J) MEK2 1S9I) revealed z-scores -6.89 -7.13, respectively, with 90.6% 86.7% residues most favored regions, confirming reliability protein models. Docking studies identified RO5126766 as a lead compound, exhibiting energies -10.1 kcal/mol -9.5 MEK2. Molecular simulations further demonstrated stability RO5126766-MEK1 RO5126766-MEK2 complexes, RMSD values ranging from 0.95 4.22 Å. The vitro anticancer assays highlighted exceptional potency RO5126766, IC50 12.87 ± 98.36 nM against MCF-7 (hormone receptor-positive breast cancer), 15.08 94.36 MDA-MB-231 (triple-negative 60.89 70.58 A549 (lung cancer). ADMET analysis confirmed high gastrointestinal absorption, favorable drug-likeness, lack blood-brain barrier permeability. In addition, indicated an optimal HOMO-LUMO energy gap (0.15816 eV), chemical hardness (0.16189 strong interactions corroborated by MEP analysis. Collectively, these findings establish potent selective inhibitor, demonstrating significant targeted agent for aggressive treatment-resistant cancers.

Язык: Английский

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Immunomodulation of Macrophages in Diabetic Wound Individuals by Structurally Diverse Bioactive Phytochemicals

Pharmaceuticals, Год журнала: 2024, Номер 17(10), С. 1294 - 1294

Опубликована: Сен. 28, 2024

Diabetes-related ulcers and slow-healing wounds pose a significant health risk to individuals due their uncertain causes. Mortality rates for diabetes foot (DFUs) range from 10% after 16 months 24% five years. The use of bioactive phytochemicals can play key role in healing predictable time. Recent literature has demonstrated that various natural substances, including flavonoids, saponins, phenolic compounds, polysaccharides, roles at different stages the wound-healing process through diverse mechanisms. These studies have categorized compounds according characteristics, bioactivities, modes action. In this study, we evaluated derived plant sources been shown crucial immunomodulation. Macrophages are closely involved immunomodulation within wound microenvironment players efferocytosis, inflammation resolution, tissue regeneration, all which contribute successful healing. Phytochemicals derivatives capabilities immune regulation, macrophage migration, nitric oxide synthase inhibition, lymphocyte T-cell stimulation, cytokine activation, killer cell enhancement, regulation NF-κβ, TNF-α, apoptosis. review, studied resolution diabetic inflammation.

Язык: Английский

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Novel targets and improved immunotherapeutic techniques with an emphasis on antimycosal drug resistance for the treatment and management of mycosis

Heliyon, Год журнала: 2024, Номер 10(16), С. e35835 - e35835

Опубликована: Авг. 1, 2024

Highlights•Antifungal drugs and their resistance development mechanism in mycosis infection.•Different metabolic path for potential targets of antifungal drugs.•The elevated risk factors, diagnosis management mycosis.•Complications assessing treatment strategies mycosis.•Updated immune therapeutics mycosis.AbstractInfections due to pathogenic fungi are endemic particular area with increased morbidity mortality. More than a thousand people infected per year the way is high demand having significant impact on population health. Medical practitioners confront various troublesome analytic therapeutical challenges administration immunosuppressed sufferer at danger expanding fungal infections. An upgraded antimycosal fundamental fruitful result while treating intrusive mycoses. A collection keeps developing specific including cell membrane, mitochondria, wall, deoxyribonucleic acid (DNA)/ribonucleic (RNA) or protein biosynthesis. Some classes ordinarily directed medications polyenes, amphotericin B, syringomycin, allylamines, honokiol, azoles, flucytosine, echinocandins etc. However, few immunotherapy processes vaccinations being developed mark this need, although one presently can't seem arrive conclusion. In review article, there has been trial give details upgradation about current therapeutic techniques vaccination against prevention as well difficulties related turn events. There also visualization mentioned paper assorted target analysis along interventions.Graphical abstractGraphical representation immunotherapeutic methods mycosis.

Язык: Английский

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Structure-Based Virtual Screening, ADMET prediction and Molecular Dynamics simulation of isoindolin-1-one scaffolds as potential inhibitors of MNK2

Опубликована: Дек. 11, 2024

Mitogen-activated protein kinase 2 (MNK2) is a promising target for various types of cancers. It activates the oncogene eukaryotic initiation factor 4E (eIF4E) by phosphorylation. Isoindolin-1-one scaffolds displayed significant anti-cancer activity as reported previously in research papers. In this study, we explored potential inhibition substituted isoindolin-1-one compounds against MNK2 through silico studies. Structure-based virtual screening library 180 having scaffold was done followed fragment molecular orbital (FMO) calculations and dynamics simulation (MDS) best two scored docked poses (compounds 132 160). The docking protocol validated superimposing co-crystal ligand. Then, ADMET prediction 160 were performed. Sixteen showed scores higher than or equal to ligand hydrogen bonding with MET162 residue. A 100 ns compound excellent 95% bond occupancy residue showing remarkable pose stability throughout simulation. Further, falls under satisfactory range. Compound exhibited protein. Thus, studies these isoindolin-1-ones will be helpful development highly potent selective inhibitors.

Язык: Английский

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Interplay of calcium, Vitamin D, and parathormone in the milieu of infections and immunity: reassessed in the context of COVID-19

The Journal of Steroid Biochemistry and Molecular Biology, Год журнала: 2024, Номер 245, С. 106624 - 106624

Опубликована: Окт. 9, 2024

Язык: Английский

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