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

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

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Abbreviations, acronyms, combos of letters and numbers… Biology is probably crawling with hundreds of codes that are often difficult to understand for none experts in the field or for scientific beginners. The best is to illustrate that with 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 cell division cycle control and in a set of specific functions, during cell signal transduction, by interacting with other proteins. Cdc37 is Hsp90 co-chaperone.

Hsp90-Cdc37 complex, one of the best described protein-protein interactions from the interactome, is involved in the control of many cellular processes and represent an attractive target for the pharmaceutical industry. Many of inhibitors have already entered clinical trials for cancer treatment.

This article from Lei Wang is a nice case-study to illustrate how new Hsp90-Cdc37 inhibitors can be identified. Everything 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. Combining several in-vitro assays, to determine IC50 values, and techniques such as Western-Blot and protein pull down, to assess complex disruption, promising compounds were identified.

Do not be scared anymore by abbreviations and acronyms! At the end of the day, the most important is to catch the science behind such terms. You have now everything in hand to prepare your assay to screen 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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