Literature DB >> 20591508

Exploring the chemical space of gamma-secretase modulators.

Heiko Zettl1, Sascha Weggen, Petra Schneider, Gisbert Schneider.   

Abstract

gamma-Secretase is a key enzyme in the pathophysiology of Alzheimer's disease (AD) and is responsible for the production of potentially toxic amyloid-beta (Abeta) 42 peptides. gamma-Secretase modulators (GSMs) are small molecules (<600 Da) causing a product shift from Abeta42 toward shorter and less toxic Abeta fragments. Classical non-steroidal anti-inflammatory drugs (NSAIDs) constituted the first class of GSMs, and therefore many of today's GSMs exhibit NSAID-like overall structure combining an acidic head group with a lipophilic backbone. Recent developments include structurally different non-acidic GSMs. Here we summarize common structural features of GSMs, pick up the controversial discussion regarding their mechanism of action, and show how computational analysis of pharmacophoric features can help reveal their pharmacological profile. Copyright 2010 Elsevier Ltd. All rights reserved.

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Year:  2010        PMID： 20591508     DOI： 10.1016/j.tips.2010.05.007

Source DB:  PubMed          Journal:  Trends Pharmacol Sci        ISSN： 0165-6147            Impact factor:   14.819


  9 in total

1.  Substrate sequence influences γ-secretase modulator activity, role of the transmembrane domain of the amyloid precursor protein.

Authors:  Sarah A Sagi; Christian B Lessard; Kellen D Winden; Hiroko Maruyama; Jeremy C Koo; Sascha Weggen; Thomas L Kukar; Todd E Golde; Edward H Koo
Journal:  J Biol Chem       Date:  2011-08-25       Impact factor: 5.157

2.  Embedded in the Membrane: How Lipids Confer Activity and Specificity to Intramembrane Proteases.

Authors:  Sandra Paschkowsky; Felix Oestereich; Lisa Marie Munter
Journal:  J Membr Biol       Date:  2017-12-19       Impact factor: 1.843

3.  NSAID-based γ-secretase modulators do not bind to the amyloid-β polypeptide.

Authors:  Paul J Barrett; Charles R Sanders; Stephen A Kaufman; Klaus Michelsen; John B Jordan
Journal:  Biochemistry       Date:  2011-11-02       Impact factor: 3.162

4.  Competition between homodimerization and cholesterol binding to the C99 domain of the amyloid precursor protein.

Authors:  Yuanli Song; Eric J Hustedt; Suzanne Brandon; Charles R Sanders
Journal:  Biochemistry       Date:  2013-07-18       Impact factor: 3.162

5.  γ-Secretase modulator (GSM) photoaffinity probes reveal distinct allosteric binding sites on presenilin.

Authors:  Nikolay Pozdnyakov; Heather E Murrey; Christina J Crump; Martin Pettersson; T Eric Ballard; Christopher W Am Ende; Kwangwook Ahn; Yue-Ming Li; Kelly R Bales; Douglas S Johnson
Journal:  J Biol Chem       Date:  2013-02-08       Impact factor: 5.157

6.  DOGS: reaction-driven de novo design of bioactive compounds.

Authors:  Markus Hartenfeller; Heiko Zettl; Miriam Walter; Matthias Rupp; Felix Reisen; Ewgenij Proschak; Sascha Weggen; Holger Stark; Gisbert Schneider
Journal:  PLoS Comput Biol       Date:  2012-02-16       Impact factor: 4.475

7.  Pharmacological targeting of the β-amyloid precursor protein intracellular domain.

Authors:  Caterina Branca; Ilenia Sarnico; Roberta Ruotolo; Annamaria Lanzillotta; Arturo Roberto Viscomi; Marina Benarese; Vanessa Porrini; Luca Lorenzini; Laura Calzà; Bruno Pietro Imbimbo; Simone Ottonello; Marina Pizzi
Journal:  Sci Rep       Date:  2014-04-09       Impact factor: 4.379

8.  γ-Secretase Modulators: Can We Combine Potency with Safety?

Authors:  Harrie J M Gijsen; Marc Mercken
Journal:  Int J Alzheimers Dis       Date:  2012-12-17

9.  Amyloid Precursor Protein Translation Is Regulated by a 3'UTR Guanine Quadruplex.

Authors:  Ezekiel Crenshaw; Brian P Leung; Chun Kit Kwok; Michal Sharoni; Kalee Olson; Neeraj P Sebastian; Sara Ansaloni; Reinhard Schweitzer-Stenner; Michael R Akins; Philip C Bevilacqua; Aleister J Saunders
Journal:  PLoS One       Date:  2015-11-30       Impact factor: 3.240
  9 in total

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