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Review
, 33 (8), 1582-1614

Discovery and Resupply of Pharmacologically Active Plant-Derived Natural Products: A Review

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Review

Discovery and Resupply of Pharmacologically Active Plant-Derived Natural Products: A Review

Atanas G Atanasov et al. Biotechnol Adv.

Abstract

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a "screening hit" through a "drug lead" to a "marketed drug" is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

Keywords: Computer modeling; Drug discovery; Ethnopharmacology; Medicine; Natural products; Organic synthesis; Pharmacology; Phytochemistry; Plant biotechnology; Plants.

Figures

Fig. 1
Fig. 1
PubMed publication trend analysis, demonstrating increased scientific interest in plant-derived natural product pharmacology, chemistry, and drug discovery. The data were retrieved with MEDSUM (http://webtools.mf.uni-lj.si/public/medsum.html) on 15th of June 2015, and cover the time period 1982–2012 (newer data are not included because of the lack of coverage). As indicated, the used search keywords were plant chemistry, plant pharmacology, plant natural product, plant compound, plant drug discovery, plant bioactivity, and the total number of PubMed publications per year was retrieved by search with the symbol *. The trend analysis reveals that the increase of PubMed citations in the target areas is faster than the increase in the total number of annual PubMed citations (indicated by the steeper slopes of the respective trend lines).
Fig. 2
Fig. 2
(A) Two molecules of magnolol concomitantly occupying the binding site of PPARγ (PDB 3R5N) are shown, with the chemical interaction pattern that defines the activity of the molecules depicted. Yellow spheres represent hydrophobic interactions, red and green arrows mark hydrogen bond acceptor and donor atoms. This interaction pattern may be converted into a structure-based pharmacophore model and used for virtual screening. (B) The empty binding pocket of PPARγ is shown, which can be used in docking simulations to place new molecules into the binding site and to calculate the binding free energy of the ligand.
Fig. 3
Fig. 3
The forward pharmacology and reverse pharmacology approaches in natural product-based drug discovery.
Fig. 4
Fig. 4
Scheme of the isoprenoid biosynthetic pathway with a focus on the biosynthesis of paclitaxel and artemisinin. Dotted arrows indicate multiple enzymatic steps. The content of the scheme is adapted from: (Lange and Ahkami, 2013; Malik et al., 2011; Paddon and Keasling, 2014).
Fig. 5
Fig. 5
Synthesis of galanthamine. The colors indicate: blue (skeletal atoms/bonds: carbon/oxygen/nitrogen framework), and red (installed non-skeletal atoms/bonds).
Fig. 6
Fig. 6
Synthesis of ingenol. The colors indicate: blue (skeletal atoms/bonds: carbon-only framework from cyclase phase), red (installed non-skeletal atoms/bonds: hydroxy functionality set up during oxidase phase), and green (installed non-skeletal atoms/bonds: functionality set up outside oxidase phase).

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