Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer’s Disease

Abstract

The multifactorial nature of Alzheimer’s disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of “multi-target-directed ligands” (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors ( 5 , 6 , and 12 ), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 μM), confirming the design rationale.

Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases

“…It is unlikely that targeting a single change will be effective at treating neurodegeneration, as several changes occur in the development of NDs. Given this multifactorial profile, NDs require a multi-target therapeutic approach, and current research is exploring multitarget drugs that can address more than a single event at the same time [44][45][46][47].…”

“…Ultimately, the drug discovery paradigm of NDs has gradually shifted from the design of selective drugs targeting a single pathophysiological pathway toward the development of multitarget agents directed at complex pathophysiological pathways of the diseases [44][45][46][47]. Indeed, the complexity and multiple etiologies of NDs make it challenging to obtain desirable therapeutic effects using single-target drugs.…”

Evaluation of selected carotenoids of Lycopersicon esculentum variants as therapeutic targets for ‘Alzheimer’s disease: an in silico approach

“…The current lack of cure for Alzheimer's disease poses a major challenge because many anticholinesterase drugs such as memantine only ameliorate the symptoms of the dementia and are not capable of preventing the progression of the disease [42,50]. There is a huge limitation and set-back in the discovery of an effective drug candidate due to the failed clinical trials of the drugs.…”

“…There is a huge limitation and set-back in the discovery of an effective drug candidate due to the failed clinical trials of the drugs. Attention is currently being focused on natural plant products for the management of the disease due to their low toxicity; while new research innovations are being developed to tailor these phytochemicals into therapeutic agents for neurodegenerative diseases [25,42]. To this effect, the role of multi-target drug candidates for multifunctional Alzheimer's disease using cholinesterase inhibition and others, for example N-methyl-D-aspartic acid receptor (NMDAR), as molecular targets has been explored [19,20,47]; however, several challenges which include undesirable side effects, incessant incidence of drug resistance, and reduced efficacy against diseases for which pathogenesis relies on many biochemical events and bioreceptors working concomitantly necessitate the need for the design of sensitive drugs with specific targets [31].…”

The Specificity and Broad Multitarget Properties of Ligands for the Free Fatty Acid Receptors FFA3/GPR41 and FFA2/GPR43 and the Related Hydroxycarboxylic Acid Receptor HCA2/GPR109A

“…Rationally designed polypharmacological studies using a set of ligands or multi-target directed ligands have been proposed as the only approach that can confront the complexity of multifactorial diseases, e.g., Alzheimer's disease [25][26][27][28][29].…”