Structural Dynamics-Driven Discovery of Anticancer and Antimetastatic Effects of Diltiazem and Glibenclamide Targeting Urokinase Receptor

Diltiazem and glibenclamide are commonly used hypotensive
and antidiabetic
drugs. This study reports the discovery of the potential antitumor
and antimetastatic effects of these two drugs using a structural dynamics-driven
virtual screening targeting urokinase receptor (uPAR). Owing to uPAR’s
high flexibility, currently resolved crystal structures of uPAR, all
in ligand-bound states, provide limited representations of its physiological
conformation. To improve the accuracy of screening, we performed a
long-timescale molecular dynamics simulation and obtained the representative
conformations of apo-uPAR as the targets for our screening. Experimentally,
we demonstrated that diltiazem and glibenclamide bound uPAR with KD values in the micromolar range. In addition,
both compounds effectively suppressed tumor growth and metastasis
in a uPAR-dependent manner in vitro and in
vivo. This work not only provides two potent uPAR inhibitors
but also reports a proof-of-concept study on the potential off-label
antitumor and antimetastatic uses of diltiazem and glibenclamide.