Drug discovery from natural products - Old problems and novel solutions for the treatment of neurodegenerative diseases

Abstract

The use of natural products has been shown to be a fruitful approach in the discovery of novel pharmaceuticals. In fact, many currently approved drugs originated from compounds that were first identified in nature. Chemical diversity of natural compounds cannot be matched by man-made libraries of chemically synthesized molecules. Many natural compounds interact with and modulate regulatory protein targets and can be considered evolutionarily-optimized drug-like molecules. Despite this, many pharmaceutical companies have reduced or eliminated their natural product discovery programs in the last two decades. Screening natural products for pharmacologically active compounds is a challenging task that requires high resource commitment. Novel approaches at the early stage of the drug discovery pipeline are needed to allow for rapid screening and identification of the most promising molecules. Here, we review the possible evolutionary roots for drug-like characteristics of numerous natural compounds. Since many of these compounds target evolutionarily conserved cellular signaling pathways, we propose novel, early-stage drug discovery approaches to identify drug candidates that can be used for the potential prevention and treatment of neurodegenerative diseases. Invertebrate in vivo animal models of neurodegenerative diseases and innovative tools used within these models are proposed here as a screening funnel to identify new drug candidates and to shuttle these hits into further stages of the drug discovery pipeline.

Keywords: Drug discovery; Immobilized transmembrane proteins; Natural products; Neurodegenerative disease; Specialized metabolites.

Figure 1.

Examples of natural compounds possessing electrophilic centers (α,β-unsaturated carbonyl groups) that can react as Michael acceptors: (a) zerumbone (terpenoid), (b) α-santonin (terpenoid), (c) 13-EFOX-L₂ (linoleic acid electrophilic oxo-derivative), (d) apigenin (flavone), and (e) nobiletin (flavone).

Figure 2.

Biosynthesis of terpenoids via mevalonate (MVA) and non-mevalonate pathway (MEP) in plants. Reused from Yang et al. [43] in accordance with the Creative Commons Attribution (CC BY) license.

Figure 3.

The comparison between the plant jasmonate hormones and orthologous mammalian eicosanoids. Reproduced with permission from [48].

Figure 4.

Figure (a) Fully assembled cell membrane affinity chromatography column after packing IAM particles with the immobilized cell membrane fragments into a glass column; (b) Frontal chromatograms of (a) increasing concentrations of [3H]-epibatidine (A =240 pM, B=150 pM, C=100 pM, D=80 pM and E=60 pM) on the α3β4α5 nicotinic receptor column. Panel (b) reproduced with permission from [76].

Figure 5.

(a) Overview of cell membrane encapsulated nanoparticles formation: (1) cells expressing targeted proteins, (2) iron oxide nanoparticles, (3) cell membrane fragments obtained after cell lysis, and (4) cell membrane encapsulated nanoparticles; (b) typical transmission electron miscroscope image of cell membrane encapsulated nanoparticles. Panel (a) reproduced with permission from [77].

Figure 6.

Drosophila models of neurodegenerative diseases in the identification of neuroprotective compounds from natural products.

Figure 7.

C. elegans models of neurodegenerative diseases in the identification of neuroprotective compounds from natural products.