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Combined In-Solution Fragment Screening and Crystallographic Binding-Mode Analysis with a Two-Domain Hsp70 Construct
Markus Zehe1, Josef Kehrein1, Curd Schollmayer1
1University of Würzburg, Institute of Pharmacy and Food Chemistry, Am Hubland, DE-97074 Würzburg, Germany.
ACS Chemical Biology
|February 6, 2024
Summary
Researchers explored novel ways to inhibit Heat shock protein 70 (Hsp70) for cancer therapy. They identified fragment binders in a key pocket, offering a new strategy for developing Hsp70 inhibitors.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Heat shock protein 70 (Hsp70) is crucial for protein homeostasis and cell death.
- Hsp70 is a promising cancer target, but developing inhibitors has been challenging.
- Existing therapeutic strategies targeting Hsp70 have not yet yielded approved drugs.
Purpose of the Study:
- To identify novel starting points for Hsp70 inhibitor development.
- To explore fragment-based screening as an alternative approach for Hsp70 drug discovery.
- To investigate potential dual inhibitors for Hsp70 and Hsp90.
Main Methods:
- Fragment-based screening using in-solution NMR.
- X-ray crystallography for structural analysis.
- Mixed-solvent molecular dynamics simulations.
Main Results:
- Fragment screening identified binders in both domains of the Hsp70 construct.
- A significant fragment hit was found in a buried pocket of the substrate-binding domain.
- This binding site is critical for inter-domain communication within Hsp70.
Conclusions:
- Fragment screening provides a viable alternative for Hsp70 inhibitor development.
- The identified fragment in the substrate-binding domain is a promising lead for novel therapeutics.
- This fragment may serve as a basis for developing dual Hsp70/Hsp90 inhibitors.
