Molecular dynamics simulations depict structural motions of the whole human aryl hydrocarbon receptor influencing its binding of ligands and HSP90

Rosales‐Hernández, Martha Cecilia; Bello, Martiniano; Toledano, Jazziel Velazquez; Feregrino, Barbara Citlali Escudero; Correa-Basurto, José; Morales, Leticia Guadalupe Fragoso; Torres-Ramos, Mónica

doi:10.1080/07391102.2023.2171132

Cited by 3 publications

(1 citation statement)

References 81 publications

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“…This allows for the phosphorylation of HSP90 and AhR. This phosphorylation facilitates the translocation of AhR to the nucleus. ,, In the nucleus, AhR forms a complex with its binding to its nuclear partner ARNT, and together they bind to DNA and regulate the expression of various target genes . In the present work, a combination of classical molecular dynamics (MD) and well-tempered metadynamics simulations was employed to investigate the structural changes that occur in the α1 and α2 helices from the basic helix–loop–helix (bHLH) domain of AhR in the cytosol.…”

Section: Resultsmentioning

confidence: 99%

Investigating the Aryl Hydrocarbon Receptor Agonist/Antagonist Conformational Switch Using Well-Tempered Metadynamics Simulations

Mosa,

AlRawashdeh,

El-Kadi

et al. 2024

J. Chem. Inf. Model.

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The aryl hydrocarbon receptor (AhR) is a liganddependent transcription factor that mediates biological signals to control various complicated cellular functions. It plays a crucial role in environmental sensing and xenobiotic metabolism. Dysregulation of AhR is associated with health concerns, including cancer and immune system disorders. Upon binding to AhR ligands, AhR, along with heat shock protein 90 and other partner proteins undergoes a transformation in the nucleus, heterodimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT), and mediates numerous biological functions by inducing the transcription of various AhR-responsive genes. In this manuscript, the 3-dimensional structure of the entire human AhR is obtained using an artificial intelligence tool, and molecular dynamics (MD) simulations are performed to study different structural conformations. These conformations provide insights into the protein's function and movement in response to ligand binding. Understanding the dynamic behavior of AhR will contribute to the development of targeted therapies for associated health conditions. Therefore, we employ well-tempered metadynamics (WTE-metaD) simulations to explore the conformational landscape of AhR and obtain a better understanding of its functional behavior. Our computational results are in excellent agreement with previous experimental findings, revealing the closed and open states of helix α1 in the basic helix−loop−helix (bHLH domain) in the cytoplasm at the atomic level. We also predict the inactive form of AhR and identify Arginine 42 as a key residue that regulates switching between closed and open conformations in existing AhR modulators.

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Section: Resultsmentioning

confidence: 99%

Investigating the Aryl Hydrocarbon Receptor Agonist/Antagonist Conformational Switch Using Well-Tempered Metadynamics Simulations

Mosa,

AlRawashdeh,

El-Kadi

et al. 2024

J. Chem. Inf. Model.

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Probing some recent natural compounds from Phellinus baumii , Colletotrichum sp. and Ligustrum lucidum as heat shock protein 90 inhibitors

Erdoğan

2023

Journal of Biomolecular Structure and Dynamics

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Drug repurposing against fucosyltransferase-2 via docking, STD-NMR, and molecular dynamic simulation studies

Atif,

Zafar,

Wahab

et al. 2024

PLoS ONE

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Aberrant fucosylation is the hallmark of malignant cell transformation, leading to many cellular events, such as uncontrolled cell proliferation, angiogenesis, tumor cell invasion, and metastasis. This increased fucosylation is caused due to the over-expression of fucosyltransferases (FUTs) that catalyzes the transfer of the fucose (Fuc) residue from GDP-fucose (donor substrate) to various oligosaccharides, glycoproteins, and glycolipids (acceptor substrates). Hence, fucosyltransferases (FUTs) are considered as validated target for the drug discovery against on cancers. In the current study, a drug repurposing approach was deployed to identify new hits against fucosyltransferase 2 (FUT2), using computational and biophysical techniques. A library of 500 US-FDA approved drugs were screened in-silico against fucosyltransferase 2 (FUT2) donor and acceptor sites. Five drugs were predicted as hits, based on their significant docking scores (-5.8 to -8.2), and binding energies (-43 to -51.19 Kcal/mol). Furthermore, STD-NMR highlighted the epitope of these drugs in the binding site of fucosyltransferase 2 (FUT2). Simulation studies provided insights about the binding site of these drugs, and 4 of them, acarbose, ascorbic acid, ibuprofen, and enalaprilat dihydrate, were found as significant binders at the donor binding site of fucosyltransferase 2 (FUT2). Hence, the current study reports the repurposed drugs as potential hits against fucosyltransferase 2 (FUT2). These may be further studied through in-vitro and in-vivo inhibitory and mechanistic studies.

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Molecular dynamics simulations depict structural motions of the whole human aryl hydrocarbon receptor influencing its binding of ligands and HSP90

Cited by 3 publications

References 81 publications

Investigating the Aryl Hydrocarbon Receptor Agonist/Antagonist Conformational Switch Using Well-Tempered Metadynamics Simulations

Investigating the Aryl Hydrocarbon Receptor Agonist/Antagonist Conformational Switch Using Well-Tempered Metadynamics Simulations

Probing some recent natural compounds from Phellinus baumii , Colletotrichum sp. and Ligustrum lucidum as heat shock protein 90 inhibitors

Drug repurposing against fucosyltransferase-2 via docking, STD-NMR, and molecular dynamic simulation studies

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