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Small‐Molecule Inhibition of the uPAR ⋅ uPA Interaction by Conformational Selection by David Xu; Khuchtumur Bum‐Erdene; Julie M. Leth; Mona K. Ghozayel; Michael Ploug; Samy O. Meroueh is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

What is Small‐Molecule Inhibition of the uPAR ⋅ uPA Interaction by Conformational Selection about?

The urokinase receptor (uPAR) is a cell surface receptor that binds to the serine protease urokinase-type plasminogen activator (uPA) with high affinity. This interaction is beneficial for extravascular fibrin clearance, but it has also been associated with a broad range of pathological conditions including cancer, atherosclerosis, and kidney disease. Here, starting with a small molecule that we previously discovered by virtual screening and cheminformatics analysis, we design and synthesize several derivatives that were tested for binding and inhibition of the uPAR • uPA interaction. To confirm the binding site and establish a binding mode of the compounds, we carried out biophysical studies using uPAR mutants, among them uPAR H47CÀ N259C , a mutant previously developed to mimic the structure of uPA-bound uPAR. Remarkably, a substantial increase in potency is observed for inhibition of uPAR H47CÀ N259C binding to uPA compared to wild-type uPAR, consistent with our use of the structure of uPAR in its uPA-bound state to design smallmolecule uPAR • uPA antagonists. Combined with the biophysical studies, molecular docking followed by extensive explicitsolvent molecular dynamics simula

Who reads Small‐Molecule Inhibition of the uPAR ⋅ uPA Interaction by Conformational Selection?

Author

David Xu; Khuchtumur Bum‐Erdene; Julie M. Leth; Mona K. Ghozayel; Michael Ploug; Samy O. Meroueh

Publisher

Wiley

Published

2020

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)