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

Producción científica: Article › revisión exhaustiva

34 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	549-552
Número de páginas	4
Publicación	Bioorganic and Medicinal Chemistry Letters
Volumen	17
N.º	2
DOI	https://doi.org/10.1016/j.bmcl.2006.10.006
Estado	Published - ene 15 2007

Nota bibliográfica

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).

Financiación

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).

Financiadores
UCSF Stuart Trust Fund
Sidney Kimmel Foundation for Cancer Research
Sandler Research Foundation
EA Pharma Co., Ltd.

ASJC Scopus subject areas

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

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10.1016/j.bmcl.2006.10.006

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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.",

keywords = "Drug design, Interaction, NHERF, PDZ domain, Protein-protein",

author = "Naoaki Fujii and Haresco, \{Jose J.\} and Novak, \{Kathleen A.P.\} and Gage, \{Robert M.\} and Nicoletta Pedemonte and David Stokoe and Kuntz, \{Irwin D.\} and \{Kiplin Guy\}, R.",

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). ",

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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.

N1 - 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).

PY - 2007/1/15

Y1 - 2007/1/15

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.

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KW - Drug design

KW - Interaction

KW - NHERF

KW - PDZ domain

KW - Protein-protein

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AN - SCOPUS:33846061735

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VL - 17

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 2

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

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

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