Rational design of a nonpeptide general chemical scaffold for reversible inhibition of PDZ domain interactions.
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.
Fujii
Naoaki
N
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143, USA.
Haresco
Jose J
JJ
Novak
Kathleen A P
KA
Gage
Robert M
RM
Pedemonte
Nicoletta
N
Stokoe
David
D
Kuntz
Irwin D
ID
Guy
R Kiplin
RK
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
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