Probing binding and cellular activity of pyrrolidinone and piperidinone small molecules targeting the urokinase receptor.

ABSTRACT: The urokinase receptor (uPAR) is a cell-surface protein that is part of an intricate web of transient and tight protein interactions that promote cancer cell invasion and metastasis. Here, we evaluate the binding and biological activity of a new class of pyrrolidinone and piperidinone compounds, along with derivatives of previously-identified pyrazole and propylamine compounds. Competition assays revealed that the compounds displace a fluorescently labeled peptide (AE147-FAM) with inhibition constant (Ki ) values ranging from 6 to 63 μM. Structure-based computational pharmacophore analysis followed by extensive explicit-solvent molecular dynamics (MD) simulations and free energy calculations suggested the pyrazole-based and piperidinone-based compounds adopt different binding modes, despit

SUBMITTER: Mani T 

PROVIDER: S-EPMC4058332 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature