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Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Screening for Inhibitors of Tau Protein Aggregation into Alzheimer Paired Helical Filaments: A Ligand Based Approach Results in Successful Scaffold Hopping

Author(s): Gregor Larbig, Marcus Pickhardt, David G. Lloyd, Boris Schmidt and Eckhard Mandelkow

Volume 4 , Issue 3 , 2007

Page: [315 - 323] Pages: 9

DOI: 10.2174/156720507781077250

Price: $65

Abstract

The aggregation of tau protein into paired helical filaments is one of the hallmarks of Alzheimers disease and related dementias. We therefore continue our search for non-toxic, cell penetrating inhibitors of tau aggregation, which hold potential for brain penetration. Pickhardt et al. (2005) have reported a high throughput screen for tau aggregation inhibitors previously, which resulted in the identification of several hit classes. Here we report the identification of novel inhibitors which were not present in the initial high throughput assay. This was achieved by transformation of the high throughput screen data into the 3D relationships of virtual pharmacophores The pharmacophore models were utilized in a virtual screen of a Maybridge database. The virtual screen provided 136 hits; 19 representative hits were selected and assayed, this resulted in two novel leads with an IC50 < 13 μM. These two leads feature a novel scaffold for tau aggregation inhibitors.

Keywords: Alzheimer's disease, inhibitors, molecular modeling, protein aggregation, tau protein


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