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

doi:10.1016/j.bmcl.2006.10.006

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

Istituto "Giannina Gaslini"

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	549-552
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	17
Issue number	2
DOIs	https://doi.org/10.1016/j.bmcl.2006.10.006
Publication status	Published - Jan 15 2007

Keywords

Drug design
Interaction
NHERF
PDZ domain
Protein-protein

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Organic Chemistry
Drug Discovery
Pharmaceutical Science

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10.1016/j.bmcl.2006.10.006

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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.",

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AU - Fujii, Naoaki

AU - Haresco, Jose J.

AU - Novak, Kathleen A P

AU - Gage, Robert M.

AU - Pedemonte, Nicoletta

AU - Stokoe, David

AU - Kuntz, Irwin D.

AU - Kiplin Guy, R.

PY - 2007/1/15

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N2 - 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.

AB - 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.

KW - Drug design

KW - Interaction

KW - NHERF

KW - PDZ domain

KW - Protein-protein

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JO - Bioorganic and Medicinal Chemistry Letters

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IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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