Rational design of a nonpeptide general chemical scaffold for reversible inhibition of PDZ domain interactions.

Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143, USA.

Novel small molecules were designed to specifically target the ligand-binding pocket of a PDZ domain. Iterative molecular docking and modeling allowed the design of an indole scaffold 10a as a reversible inhibitor of ligand binding. The 10a scaffold inhibited the interaction between MAGI-3 and PTEN and showed cellular activities that are consistent with the inhibition of NHERF-1 function.

PMID: 17055267 [PubMed - indexed for MEDLINE]