title: Rational design of a nonpeptide general chemical scaffold for reversible inhibition of PDZ domain interactions.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143, USA.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Fujii
authors.forename: Jose J
authors.initials: JJ
authors.lastname: Haresco
authors.forename: Kathleen A P
authors.initials: KA
authors.lastname: Novak
authors.forename: Robert M
authors.initials: RM
authors.lastname: Gage
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pedemonte
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Kuntz
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D002460:Cell Line; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D051528:Guanylate Kinases; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D051059:PTEN Phosphohydrolase / Q000737:chemistry; D010750:Phosphoproteins / Q000037:antagonists & inhibitors; D011955:Receptors, Drug / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D008024:Ligands; D008565:Membrane Proteins; C484659:PDZK1 protein, human; D010750:Phosphoproteins; D011955:Receptors, Drug; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D051528:Guanylate Kinases; C113338:MAGI1 protein, human; D051059:PTEN Phosphohydrolase