Structure-based virtual screening and optimization of modulators targeting Hsp90-Cdc37 interaction

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Compound disruption of Hsp90-Cdc37 interaction assessed easily in-vitro

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Abbreviations, acronyms, strange combinations of letters and numbers… The field of biology is filled with numerous codes that are often difficult for non-experts and scientific beginners to understand. Let’s illustrate that point with some examples.
Hsp90 stands for “heat shock protein 90”, a chaperone protein involved in protein folding, protein stabilization against heat stress, and protein degradation.
Cdc37, encoded by the CDC37 gene, is a protein involved in controlling the cell division cycle, and in a set of specific functions during cell signal transduction by interacting with other proteins. Cdc37 is an Hsp90 co-chaperone.
One of the best described protein-protein interactions in the interactome, the Hsp90-Cdc37 complex is involved in controlling many cellular processes and represents an attractive target for the pharmaceutical industry. Many inhibitors have already entered clinical trials for cancer treatment.
This article from Lei Wang is a welcome case study that illustrates how new Hsp90-Cdc37 inhibitors can be identified. It all starts with structure-based virtual screening, including molecular docking and optimization on a set of compounds selected by in-silico SAR. The potency of the most promising compounds was then assessed with real biological experiments. Promising compounds were identified by combining several in-vitro assays to determine IC50 values, and techniques such as Western-Blot and protein pull-down to assess complex disruption.
Don’t be turned away by abbreviations and acronyms! At the end of the day, the most important thing is to grasp the science behind the terms. Now, you have everything you need to prepare your assay for screening Hsp90-Cdc37 inhibitors.

Abstract

Identification of novel Hsp90 inhibitors to disrupt Hsp90-Cdc37 protein-protein interaction (PPI) could be an alternative strategy to achieve Hsp90 inhibition. In this paper, a series of small molecules targeting Hsp90-Cdc37 complex are addressed and characterized. The molecules’ key characters are determined by utilizing a structure-based virtual screening workflow, derivatives synthesis, and biological evaluation. Structural optimization and structure-activity relationship (SAR) analysis were then carried out on the virtual hit of VS-8 with potent activity, which resulted in the discovery of compound 10 as a more potent regulator of Hsp90-Cdc37 interaction with a promising inhibitory effect (IC50 = 27 μM), a moderate binding capacity (KD = 40 μM) and a preferable antiproliferative activity against several cancer lines including MCF-7, SKBR3 and A549 cell lines (IC50 = 26 μM, 15 μM and 38 μM respectively). All the data suggest that compound 10 exhibits moderate inhibitory effect on Hsp90-Cdc37 and could be regard as a first evidence of a non-natural compound targeting Hsp90-Cdc37 PPI.

Details

European Journal of Medical Chemistry, 2017 Aug 18;136:63-73.

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