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Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
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Mebendazole's Conformational Space and Its Predicted Binding to Human Heat-Shock Protein 90
Walter Fiedler1, Fabian Freisleben1, Jasmin Wellbrock1
1Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Journal of Chemical Information and Modeling
|July 22, 2022
Summary
Mebendazole, an antiparasitic drug, may treat acute myeloid leukemia by binding to heat shock protein 90 (Hsp90). Computational studies predict mebendazole docks within the Hsp90
Area of Science:
- Computational chemistry
- Molecular modeling
- Drug discovery
Background:
- Mebendazole, an antiparasitic agent, shows potential in inhibiting acute myeloid leukemia (AML) cell growth.
- This effect is hypothesized to be mediated by binding to heat shock protein 90 (Hsp90).
Purpose of the Study:
- To computationally predict the binding poses of mebendazole within the adenosine triphosphate (ATP) binding site of Hsp90.
- To provide molecular-level insights into the interaction between mebendazole and Hsp90.
Main Methods:
- Quantum mechanics (QM) calculations at the MP2/aug-cc-pVTZ level for mebendazole tautomer optimization.
- Molecular similarity analysis to select relevant Hsp90 crystal structures.
- Extensive molecular dynamics (MD) simulations (600 ns) in explicit solvent using two force fields to identify binding poses.
Main Results:
- Identified 152 stable minima for mebendazole tautomers.
- Generated mebendazole-Hsp90 complex models.
- Discovered nine distinct binding poses of mebendazole within the Hsp90 ATP binding site through MD simulations.
Conclusions:
- Computational findings support the hypothesis that mebendazole can bind to the ATP binding site of Hsp90.
- These results lay the groundwork for further investigation of mebendazole as a potential therapeutic agent for AML.
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