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

Naoaki Fujii, Jose J. Haresco, Kathleen A P Novak, Robert M. Gage, Nicoletta Pedemonte, David Stokoe, Irwin D. Kuntz, R. Kiplin Guy

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)549-552
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume17
Issue number2
DOIs
Publication statusPublished - Jan 15 2007

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PDZ Domains
Scaffolds
Ligands
Molecules
indole
sodium-hydrogen exchanger regulatory factor

Keywords

  • Drug design
  • Interaction
  • NHERF
  • PDZ domain
  • Protein-protein

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Rational design of a nonpeptide general chemical scaffold for reversible inhibition of PDZ domain interactions. / Fujii, Naoaki; Haresco, Jose J.; Novak, Kathleen A P; Gage, Robert M.; Pedemonte, Nicoletta; Stokoe, David; Kuntz, Irwin D.; Kiplin Guy, R.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 17, No. 2, 15.01.2007, p. 549-552.

Research output: Contribution to journalArticle

Fujii, Naoaki ; Haresco, Jose J. ; Novak, Kathleen A P ; Gage, Robert M. ; Pedemonte, Nicoletta ; Stokoe, David ; Kuntz, Irwin D. ; Kiplin Guy, R. / Rational design of a nonpeptide general chemical scaffold for reversible inhibition of PDZ domain interactions. In: Bioorganic and Medicinal Chemistry Letters. 2007 ; Vol. 17, No. 2. pp. 549-552.
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