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Mebendazole’s Conformational Space and its Predicted Binding to Human Heat-Shock Protein 90

  • Recent experimental evidence suggest that mebendazole, a popular antiparasitic drug, binds to heat shock protein 90 (Hsp90) and inhibit acute myeloid leukemia cell growth. In this study we use quantum mechanics (QM), molecular similarity and molecular dynamics (MD) calculations to predict possible binding poses of mebendazole to the adenosine triphosphate (ATP) binding site of Hsp90. Extensive conformational searches and minimization of the five tautomers of mebendazole using MP2/aug-cc-pVTZ theory level resulting in 152 minima being identified. Mebendazole-Hsp90 complex models were created using the QM optimized conformations and protein coordinates obtained from experimental crystal structures that were chosen through similarity calculations. Nine different poses were identified from a total of 600 ns of explicit solvent, all-atom MD simulations using two different force fields. All simulations support the hypothesis that mebendazole is able to bind to the ATP binding site of Hsp90.

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Document Type:Preprint
Author:Walter Fiedler, Fabian Freisleben, Jasmin Wellbrock, Karl Kirschner
Number of pages:31
Publisher:Cambridge University Press
Date of first publication:2021/09/28
Copyright:The content is available under CC BY NC ND 4.0 License
Funding Information:The UBRS’s computer hardware was supported by the Federal Ministry for Education and Research and by the Ministry for Innovation, Science, Research, and Technology of the state Northrhine-Westfalia (research grant 13FH156IN6).
Keyword:AML; Drug; HSP90; Heat Shock Protein; Leukemia; Mebendazole; Molecular dynamics; Quantum mechanics; Tautomers
Departments, institutes and facilities:Fachbereich Informatik
Projects:EI-HPC - Enabling Infrastructure for HPC-Applications (DE/BMBF/13FH156IN6)
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
Entry in this database:2021/10/04
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International