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

Federica Prati,Andrea Cavalli,Maria Bolognesi

doi:10.3390/molecules21040466

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.

Highlights

The recent appreciation of the network medicine concepts has had significant implications for drug discovery, leading to the new era of multitarget drugs [1,2]
This study describes a rationally-designed molecule with a dual AChE/NR2B profile and illustrates a successful and interesting strategy for developing conceptually new multitarget-directed ligands (MTDLs), as possibly more effective and safer drug treatments over the current drug combinations commonly used in clinical practice
All of the evidence we have accumulated so far corroborates the initial conviction that modulating a multiplicity of interconnected targets with an MTDL is an asset in treating a complex disorder of the elderly, such as Alzheimer’s disease (AD)

Summary

Introduction

The recent appreciation of the network medicine concepts has had significant implications for drug discovery, leading to the new era of multitarget drugs [1,2]. Extent of the framework overlap that could be reached was in many cases low, this process resulted in large property increases that often compromised oral bioavailability [12] Against this backdrop, over the years, fragment-based drug discovery (FBDD) strategies have received increasing consensus as optimal starting points for multitarget drug design [13,14]. Over the years, fragment-based drug discovery (FBDD) strategies have received increasing consensus as optimal starting points for multitarget drug design [13,14] In this respect, in 2001, Hann and co-workers calculated the probability of interaction between proteins and ligands of diverse molecular complexity. The rest of this review is divided into two parts dealing with case studies provided by our research and inspired by the two approaches

Development of Memantine-Galantamine Hybrids via a Linking Strategy

Development of Clioquinol-Donepezil Hybrids via a Fusing Strategy

Conclusions