Abstract
Brain network dysfunction in Alzheimer’s disease (AD) involves many proteins (enzymes), processes and pathways, which overlap and influence one another in AD pathogenesis. This complexity challenges the dominant paradigm in drug discovery or a single-target drug for a single mechanism. Although this paradigm has achieved considerable success in some particular diseases, it has failed to provide effective approaches to AD therapy. Network medicines may offer alternative hope for effective treatment of AD and other complex diseases. In contrast to the single-target drug approach, network medicines employ a holistic approach to restore network dysfunction by simultaneously targeting key components in disease networks. In this paper, we explore several drugs either in the clinic or under development for AD therapy in term of their design strategies, diverse mechanisms of action and disease-modifying potential. These drugs act as multi-target ligands and may serve as leads for further development as network medicines.
Highlights
During the past two decades, drug discovery has mainly focused on the single-target paradigm, pursuing exquisitely selective ligands to drug targets with the hope of avoiding unwanted side effects
The single-target drugs are limited in the treatment of complex diseases such as cancer, depression, and Alzheimer’s disease (AD), because complex diseases have multiple pathogenic mechanisms and are not likely to result from a single defect
It has been reported that the rapidly-reversible acetylcholinesterase (AChE) inhibitors, which were intended for decreasing AChE activity, were found to significantly increase AChE activity and protein levels in the cerebrospinal fluid (CSF) of AD patients after long-term (1 year) treatment [5]
Summary
During the past two decades, drug discovery has mainly focused on the single-target paradigm (single keys for specific locks), pursuing exquisitely selective ligands to drug targets with the hope of avoiding unwanted side effects. A large number of such antagonists have been developed based on the conventional paradigm “high affinity/high specificity”, which dominates the drug discovery in the pharmaceutical industry during the past decades All such antagonists except memantine have disappointingly failed in advanced clinical trials, in large part because of unacceptable side effects [18]. Drugs with high affinity binding to NMDARs are expected to bind too tightly and end up blocking virtually all receptor activation including normal receptor activation, leading to clinically unacceptable side effects [18]. One such example is dizocilpine (MK-801), a potent NMDAR antagonist with Ki of 30.5 nM [20]. The mechanisms by which memantine exerts its clinical benefits with safe profile have attracted a great interest in the field of medicinal chemistry [18]
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