Naturally Occurring Plant‐Based Anticancerous Candidates as Potential ERK2 Inhibitors: In‐Silico Database Mining and Molecular Dynamics Simulations

Chemistry & Biodiversity, Год журнала: 2024, Номер 21(11)

Опубликована: Июль 30, 2024

Abstract The evolutionarily conserved extracellular signal‐regulated kinase 2 (ERK2) is involved in regulating cellular signaling both normal and pathological conditions. ERK2 expression critical for human development, while hyperactivation a major factor tumor progression. Up to now, there have been no approved inhibitors that target ERK2, as such, here we report on screening of naturally occurring plant‐based anticancerous compound‐activity‐target (NPACT) database prospective inhibitors. More than 1,500 phytochemicals were screened using in‐silico molecular docking dynamics (MD) approaches. NPACT compounds with score lower co‐crystallized LHZ inhibitor (calc. −10.5 kcal/mol) subjected MD simulations. Binding energies (Δ G binding ) inhibitor‐ERK2 complexes over the course estimated an MM‐GBSA approach. Based MM‐GBSA//100 ns simulations, steroid zhankuic acid C (NPACT01034) demonstrated greater affinity against protein LHZ, Δ values −50.0 −47.7 kcal/mol, respectively. Structural energetical analyses throughout stabilization complexed protein. anticipated ADMET properties indicated minimal toxicity. Moreover, evaluation fourteen clinical trials higher towards

Язык: Английский

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In silico exploration of PD-L1 binding compounds: Structure-based virtual screening, molecular docking, and MD simulation

PLoS ONE, Год журнала: 2024, Номер 19(8), С. e0306804 - e0306804

Опубликована: Авг. 9, 2024

Programmed death-ligand 1 (PD-L1), a transmembrane protein, is associated with the regulation of immune system. It frequently has overexpression in various cancers, allowing tumor cells to avoid detection. PD-L1 inhibition risen as potential strategy field therapeutic immunology for cancer. In current study, structure-based virtual screening drug libraries was conducted and then screened hits were docked active residues select optimal binding poses. The top ten compounds affinities ranging from -10.734 -10.398 kcal/mol selected further analysis. ADMET analysis showed meet criteria properties. Further, conformational changes stability two analyzed by conducting 200 ns simulation it observed that did not exert protein structure. All results suggest chosen can be considered lead biological activity vitro studies.

Язык: Английский

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Exploration of alpha-glucosidase inhibitors: A comprehensive in silico approach targeting a large set of triazole derivatives

PLoS ONE, Год журнала: 2024, Номер 19(9), С. e0308308 - e0308308

Опубликована: Сен. 6, 2024

Background The increasing prevalence of diabetes and the side effects associated with current medications necessitate development novel candidate drugs targeting alpha-glucosidase as a potential treatment option. Methods This study employed computer-aided drug design techniques to identify inhibitors from PubChem database. Molecular docking was used evaluate 81,197 compounds, narrowing set for further analysis providing insights into ligand-target interactions. An ADMET assessed pharmacokinetic properties these including absorption, distribution, metabolism, excretion, toxicity. dynamics simulations validated results. Results 9 compounds were identified based on their ability form stable complexes favorable profiles, three subjected molecular dynamics, which showed stability throughout entire 100 ns simulation. Conclusion These findings suggest promising new treatment. Further validation through in vitro vivo studies is recommended confirm efficacy safety.

Язык: Английский

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Potential MAO‐B Inhibitors from Cissampelos capensis L.f.: ADMET, Molecular Docking, Dynamics, and DFT Insights

Chemistry & Biodiversity, Год журнала: 2024, Номер unknown

Опубликована: Окт. 29, 2024

This study explores the therapeutic potential of three proaporphine alkaloids-cissamaline, cissamanine, and cissamdine, which were recently isolated from Cissampelos capensis L.f., against Parkinson's disease (PD). Using computational techniques, we investigated their efficacy as inhibitors a key protein in PD. ADMET analysis demonstrated that these alkaloids conform to Lipinski, Pfizer, Golden Triangle, GSK rules, indicating favorable safety, oral bioavailability, high probability passing human intestinal blood-brain barriers. They neither substrates nor any CYP enzymes tested, minimal metabolic interference an enhanced safety profile. Molecular docking studies revealed binding energies -9.05 kcal/mol (cissamaline), -9.95 (cissamanine), -10.65 (cissamdine) MAO-B, critical PD target, surpassing control (zonisamide, -6.96 kcal/mol). The molecular interaction analyses also promising, with interactions comparable control. dynamics (MD) simulations confirmed stable protein-ligand interactions, root-mean-square deviation (RMSD) values ranging 1.03 Å 3.92 Å, fluctuation (RMSF) remaining below 1.14 radius gyration (RGyr) between 20.20 20.50 compact structures. Hydrogen bonding maximum hydrogen bond counts 6 5 4 (cissamdine), demonstrating robust MAO-B. Density Functional Theory (DFT) calculations highest electrophilicity (ω =0.151), electron affinity (EA =0.075), smallest HOMO-LUMO gap (ΔE =0.130) for reactivity. These results advocate further vitro vivo evaluate compounds' therapeutics.

Язык: Английский

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Bioactive Small Molecules and Drug Discovery

Опубликована: Ноя. 29, 2024

Bioactive small molecules are essential for contemporary drug research, because of their capacity to interact with certain biological targets, changing function and producing therapeutic effects, important agents. The intricate process selecting bioactive in discovery involves careful consideration diverse factors, encompassing target identification, pharmacokinetics, chemical structure, safety, cost, intellectual property considerations. Complete a delicate balance among these elements is crucial identifying advancing promising candidates that hold the potential effective pharmaceutical development. In this chapter, we covered various sources importance. Along this, role computational methods also discussed special emphasis on density functional theory studies small-molecule discovery.

Язык: Английский

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Causal-inferring and molecular-docking yield new targets for malignant melanoma therapy

Archives of Dermatological Research, Год журнала: 2024, Номер 317(1)

Опубликована: Ноя. 30, 2024

Язык: Английский

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