Anti-amyloid Aggregation Activity of Natural Compounds: Implications for Alzheimer’s Drug Discovery

Abstract

Several plant-derived natural compounds are known to exhibit anti-amyloid aggregation activity which makes them attractive as potential therapies to treat Alzheimer's disease. The mechanisms of their anti-amyloid activity are not well known. In this regard, many natural compounds are known to exhibit direct binding to various amyloid species including oligomers and fibrils, which in turn can lead to conformational change in the beta-sheet assembly to form nontoxic aggregates. This review discusses the mechanism of anti-amyloid activity of 16 natural compounds and gives structural details on their direct binding interactions with amyloid aggregates. Our computational investigations show that the physicochemical properties of natural products do fit Lipinski's criteria and that catechol and catechol-type moieties present in natural compounds act as lysine site-specific inhibitors of amyloid aggregation. Based on these observations, we propose a structural template to design novel small molecules containing site-specific ring scaffolds, planar aromatic and nonaromatic linkers with suitably substituted hydrogen bond acceptors and donors. These studies will have significant implications in the design and development of novel amyloid aggregation inhibitors with superior metabolic stability and blood-brain barrier penetration as potential agents to treat Alzheimer's disease.

Alzheimer’s disease: How metal ions define β-amyloid function

“…It is notable that many promising AD drug candidates are natural compounds, implying that not only medicinal inorganic chemistry but also natural compound chemistry is currently thriving within the AD area. Only a few examples will be mentioned as this area has been reviewed extensively [17,568,570,[632][633][634].…”

How accurate are your simulations? Effects of confined aqueous volume and AMBER FF99SB and CHARMM22/CMAP force field parameters on structural ensembles of intrinsically disordered proteins: Amyloid-β42in water

“…Drugs in clinical trials that decrease the levels of Ab 42 have been proposed to be linked to a reduced risk of the AD development (see, for example, refs. [36][37][38][39][40][41] ). Various experimental studies have shown that Ab 42 possesses an increased toxicity in comparison with other Ab segments.…”

Anti-amyloid aggregation activity of novel carotenoids: implications for Alzheimer’s drug discovery

“…Aging is the main risk factor associated with AD, and the prevalence of the disease has been estimated from 0.6% to 8.4% in people at ages between 65 and 85 years 3. Clinical features of this neurodegenerative condition include slow loss of memory and reasoning skills, speech abnormalities, and disorientation 3–5. The disease culminates in the complete custodial care of the patient and finally death, which is usually caused by pneumonia 3.…”