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

Recent experimental evidence suggests that mebendazole,
a popular
antiparasitic drug, binds to heat shock protein 90 (Hsp90) and inhibits
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 mebendazole tautomers using
the MP2/aug-cc-pVTZ theory level resulted in 152 minima. Mebendazole-Hsp90
complex models were subsequently 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.