Structure-Based Discovery of a Novel Class of Small-Molecule Pure Antagonists of Integrin αVβ3.

ABSTRACT: Inhibitors of integrin αVβ3 have therapeutic promise for a variety of diseases. Most αVβ3-targeting small molecules patterned after the RGD motif are partial agonists because they induce a high-affinity, ligand-binding conformation and prime the receptor to bind the ligand without an activating stimulus, in part via a charge-charge interaction between their aspartic acid carboxyl group and the metal ion in the metal-ion-dependent adhesion site (MIDAS). Building upon our previous studies on the related integrin αIIbβ3, we searched for pure αVβ3 antagonists that lack this typical aspartic acid carboxyl group and instead engage through direct binding to one of the coordinating residues of the MIDAS metal ion, specifically β3 E220. By in silico screening of two large chemical lib

SUBMITTER: Sen S 

PROVIDER: S-EPMC9767310 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature