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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.

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|February 6, 2024
PubMed
Summary
This summary is machine-generated.

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.

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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.