Exploring the inhibition mechanism on HIF‐2 by inhibitor PT2399 and 0X3 using molecular dynamics simulations

Sun, Dongru; Wang, Zhijun; Zheng, Qing‐Chuan; Zhang, Hongxing

doi:10.1002/jmr.2730

Cited by 6 publications

(5 citation statements)

References 47 publications

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“…For the simulated complex, 500 snapshots were extracted from the last 50 ns along the MD trajectory at intervals of 100 ps. The MM/GBSA [ 47 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ] implemented in AMBER14 [ 78 ], and the electrostatic free energy of solvation (∆G GB ) were calculated by solving GB equations and computing the binding free energies of the complex systems [ 79 ]. The binding energy (ΔG GBTOT ) can be represented as follows:

where ΔG GBTOT was obtained by summing the van der Waals (ΔE vdW ) energies and the electrostatic energy (ΔE ELE ) is the sum of polar (ΔG GB ) and nonpolar (ΔG GBSUR ) contributions.…”

Section: Methodsmentioning

confidence: 99%

Prediction of GluN2B-CT1290-1310/DAPK1 Interaction by Protein–Peptide Docking and Molecular Dynamics Simulation

Yang

et al. 2018

Molecules

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The interaction of death-associated protein kinase 1 (DAPK1) with the 2B subunit (GluN2B) C-terminus of N-methyl-D-aspartate receptor (NMDAR) plays a critical role in the pathophysiology of depression and is considered a potential target for the structure-based discovery of new antidepressants. However, the 3D structures of C-terminus residues 1290–1310 of GluN2B (GluN2B-CT1290-1310) remain elusive and the interaction between GluN2B-CT1290-1310 and DAPK1 is unknown. In this study, the mechanism of interaction between DAPK1 and GluN2B-CT1290-1310 was predicted by computational simulation methods including protein–peptide docking and molecular dynamics (MD) simulation. Based on the equilibrated MD trajectory, the total binding free energy between GluN2B-CT1290-1310 and DAPK1 was computed by the mechanics generalized born surface area (MM/GBSA) approach. The simulation results showed that hydrophobic, van der Waals, and electrostatic interactions are responsible for the binding of GluN2B-CT1290–1310/DAPK1. Moreover, through per-residue free energy decomposition and in silico alanine scanning analysis, hotspot residues between GluN2B-CT1290-1310 and DAPK1 interface were identified. In conclusion, this work predicted the binding mode and quantitatively characterized the protein–peptide interface, which will aid in the discovery of novel drugs targeting the GluN2B-CT1290-1310 and DAPK1 interface.

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where ΔG GBTOT was obtained by summing the van der Waals (ΔE vdW ) energies and the electrostatic energy (ΔE ELE ) is the sum of polar (ΔG GB ) and nonpolar (ΔG GBSUR ) contributions.…”

Section: Methodsmentioning

confidence: 99%

Prediction of GluN2B-CT1290-1310/DAPK1 Interaction by Protein–Peptide Docking and Molecular Dynamics Simulation

Yang

et al. 2018

Molecules

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“…Co-and chromatin-immunoprecipitation (ChIP) experiments have demonstrated disruption of HIF heterodimer formation and prevention of HRE binding [81]. Although molecular dynamics simulations revealed an interruption of crucial hydrophobic interactions within the HIF-2 dimer for the inhibitors PT2399 and 0X3, this has to be further verified in vivo [82]. State-of-the-art live cell microscopy could further elucidate mechanisms of action.…”

Section: Inhibitors Of Hif-α/β Dimerization and Transcription Complexmentioning

confidence: 99%

Ways into Understanding HIF Inhibition

Schönberger

Fandrey

Prost-Fingerle

2021

Cancers

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Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging field of cancer research. Several drug candidates target protein–protein interactions or transcription mechanisms of the HIF pathway in order to interfere with activation of this pathway, which is deregulated in a wide range of solid and liquid cancers. Although some inhibitors are already in clinical trials, open questions remain with respect to their modes of action. New imaging technologies using luminescent and fluorescent methods or nanobodies to complement widely used approaches such as chromatin immunoprecipitation may help to answer some of these questions. In this review, we aim to summarize current inhibitor classes targeting the HIF pathway and to provide an overview of in vitro and in vivo techniques that could improve the understanding of inhibitor mechanisms. Unravelling the distinct principles regarding how inhibitors work is an indispensable step for efficient clinical applications and safety of anticancer compounds.

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“…The most representative HIF-2α-targeted therapies are PT2385 and PT2399 in renal cell carcinoma (12). PT2385 prevents the dimerization of HIF-2α and ARNT/HIF-1β, while PT2399 directly binds to the HIF-2α PAS B domain (11,13). PT2385 was utilized not only in renal cell carcinoma, but also in liver cancer.…”

Section: Hif-2α As An Oncogenementioning

confidence: 99%

“…Currently, the most mature applications involve HIF-2α/VEGF axis-targeted treatments in renal cell carcinoma. HIF-2α inhibitors, such as PT2385 and PT2399, were assessed in phase III clinical trials and were found to be effective for clear-cell renal cell carcinoma treatment (12,13). HIF-2α plays an important role not only in tumours, but also in other diseases.…”

Section: Introductionmentioning

confidence: 99%

Role of hypoxia‑inducible factor‑2α in lung cancer (Review)

et al. 2021

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Hypoxia is a common phenomenon during tumorigenesis and tumour development. In recent years, studies have found that hypoxia-inducible factor (HIF)-2α, also referred to as endothelial PAS domain protein-1, plays an important role in tumours. HIF-2α is an important oncogene and a critical prognostic indicator in non-small cell lung cancer. However, no unified conclusion can be drawn concerning HIF-2α and small cell lung cancer, since few studies to date have focused on their association. An increasing number of studies have confirmed that HIF-2α is involved in tumorigenesis, cell proliferation, angiogenesis, metastasis, drug resistance and radiotherapy failure in lung cancer. Of note, HIF-2α plays a crucial role in lung cancer to maintain cancer cell stemness. Based on the importance of HIF-2α in lung cancer, HIF-2α-targeted therapy has been attracting increasing attention. Although this strategy currently appears to be promising in vitro, it has never been assessed as a therapy for lung cancer. The aim of the present review was to summarize the contribution of HIF-2α to various aspects of lung cancer, as well as its potential as targeted therapy. Contents 1. Introduction 2. HIF-2α as an oncogene 3. HIF-2α in lung cancer 4. Conclusion and perspectives

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Exploring the inhibition mechanism on HIF‐2 by inhibitor PT2399 and 0X3 using molecular dynamics simulations

Cited by 6 publications

References 47 publications

Prediction of GluN2B-CT1290-1310/DAPK1 Interaction by Protein–Peptide Docking and Molecular Dynamics Simulation

Prediction of GluN2B-CT1290-1310/DAPK1 Interaction by Protein–Peptide Docking and Molecular Dynamics Simulation

Ways into Understanding HIF Inhibition

Role of hypoxia‑inducible factor‑2α in lung cancer (Review)

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