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Molecules 2016, 21(4), 466; doi:10.3390/molecules21040466

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

1
Department of Pharmacy and Biotechnology, Alma Mater Studiorum—University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy
2
Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
3
Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genova, Italy
*
Authors to whom correspondence should be addressed.
Academic Editors: Michael Decker and Diego Muñoz-Torrero
Received: 9 March 2016 / Revised: 3 April 2016 / Accepted: 5 April 2016 / Published: 8 April 2016
(This article belongs to the Special Issue Molecules against Alzheimer)
View Full-Text   |   Download PDF [1238 KB, uploaded 8 April 2016]   |  

Abstract

Multitarget drug discovery is one of the hottest topics and most active fields in the search for new molecules against Alzheimer’s disease (AD). Over the last 20 years, many promising multitarget-directed ligands (MTDLs) have been identified and developed at a pre-clinical level. However, how to design them in a rational way remains the most fundamental challenge of medicinal chemists. This is related to the foundational question of achieving an optimized activity towards multiple targets of interest, while preserving drug-like properties. In this respect, large hybrid molecules and small fragments are poles apart. In this review article, our aim is to appraise what we have accomplished in the development of both hybrid- and fragment-like molecules directed to diverse AD targets (i.e., acetylcholinesterase, NMDA receptors, metal chelation, BACE-1 and GSK-3β). In addition, we attempt to highlight what are the persistent needs that deserve to be improved and cared for, with the ultimate goal of moving an MTDL to AD clinical studies. View Full-Text
Keywords: multitarget drug discovery; galantamine; memantine; donepezil; clioquinol; BACE-1 inhibitors; GSK-3β inhibitors multitarget drug discovery; galantamine; memantine; donepezil; clioquinol; BACE-1 inhibitors; GSK-3β inhibitors
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Prati, F.; Cavalli, A.; Bolognesi, M.L. Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease. Molecules 2016, 21, 466.

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