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 journalArticlepeer-review

33 Scopus citations

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
StatePublished - Jan 15 2007

Bibliographical note

Funding Information:
We thank Angela McArthur for scientific editing of the manuscript. Financial support was provided in part by the Fujisawa Pharmaceutical Co., Ltd. (NF), the UCSF Stuart Trust Fund (NF, KAN, RKG), the Sandler Research Foundation, and the Sidney Kimmel Research Foundation (NF, RKG).

Keywords

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

ASJC Scopus subject areas

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

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