Natural product drug discovery

This article describes the utilization of natural resources in the process of finding new drug compounds, an approach commonly referred to as "natural product drug discovery". Together with synthetic chemistry, they represent complementary strategies for lead identification in drug discovery.

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Introduction

Before 20th century, crude and semi-pure extracts of plants, animals, microbes and minerals represented the only medications available to treat human and domestic animal illnesses. The 20th century revolutionized the thinking in the use of drugs, as the receptor theory of drug action was postulated in ?. The idea that effect of drug in human body are mediated by specific interactions of the drug molecule with biological macromolecules, (proteins or nucleic acids in most cases) led scientists to the conclusion that individual chemical compounds in extracts, rather than some mystical “power of life” are the factors required for the biological activity of the drug. This made for the beginning of a totally new era in pharmacology, as pure, isolated chemicals, instead of extracts, became the standard treatments for diseases. Indeed, many bioactive compounds, responsible for the effects of crude extract drugs, and their chemical structure was elucidated. Classical examples of drug compounds discovered this way are morphine, the active agent in opium, and digoxin, a heart stimulant originating from flower Digitalis lanata. The evolution in synthetic chemistry also led to chemical synthesis of many of the elucidated structures.

Indeed, the 20th century brought up several new drug compounds, and until the 1970s, the new drug compounds were almost solely of natural origin. However, as the fields of synthetic chemistry became more and more powerful, the pharmaceutical industry started to prefer synthetic compounds instead of natural products as drug candidates. The following reasons for the decline in interest in natural products as drug candidates have been suggested: ^[1]

• introduction of high-throughput screening (HTS) as the standard method for hit discovery. The traditional natural product libraries were poorly suitable for HTS environment.
• the pressure to faster generation of lead compounds. The process in natural product drug discovery usually required several separation circles and structure elucidation (see below) and was thus time-consuming.
• rise of combinatorial chemistry and thus the generation of synthetic compound libraries in a screening friendly format
• general decline in interest towards developing new antibiotic drugs, a traditionally strong area of natural product drug discovery.

However, more recent evolvements in techniques involved in natural product research, as well as the observation of the chemical complementarity of natural and synthetic compounds, have restored the interest in natural compounds as drug candidates. The declining trend in patents on natural products has turned as a slight increase in the beginning of the 21st century.

Nature as source of drug compounds

Despite the rise of combinatorial chemistry as an integral part of lead discovery process, the natural products still play a major role as starting material for drug discovery.^[2] David Newman and Gordon Cragg have made a remarkable contribution to evaluation of the significance of natural products in drug discovery via their analysis of the sources of approved drugs. The latest update of the report was published in 2007 ^[3], covering years 1981-2006. Acoording to their report, of the 974 small molecule new chemical entities, 63% were natural derived or nature-inspired (semisynthetic derivatives of natural products, compounds synthesised by use of natural product pharmacophore or compounds otherwise designed to mimic the natural ligand/substrate of the target). For certain therapy areas, such as antimicrobials, anticancer antihypertensive and anti-inflammatory drugs, the numbers were even higher (for instance, approximately 75% of all approved small molecule new chemical entities were derived from nature.

Natural products have been especially successful as lead structures for antibacterial therapies.^[4]

A potential explanation beyond the success of natural products as drugs is the classification of natural compounds as so-called privileged structures. This concept is based on the fact that chemical agents produced by living organisms (particularly the secondary metabolites) have evolved throughout millenniums under the evolutionary pressure, and are therefore more likely to have a specific biological activity than “randomly” assembled, man-made synthetic chemicals. Despite the enormous potential, only a minor oart of globe’s living species has ever been tested for any bioactivity. For instance, approximately only 10% of all existing plant species has been assayed, and in the case of microbes the value is even lower.

Plant-derived bioactive material

The vast majority of traditionally used crude drugs have been plant-derived extracts. This has resulted in an inherited pool of information of the healing potential of plant species, thus making them important source of starting material for drug discovery. A different set of metabolites is usually produced in the different anatomical parts of the plant (e.. root, leaves and flower), and botanical knowledge is crucial also for the correct taxonomical determination of the identified bioactive plants.

Microbial species with bioactive metabolites

In the microbial world, there is an ongoing, everlasting competition of living space and nutritients. To survive in these conditions, many microbes have developed abilities to prevent competing species from proliferation. This phenomenon has been translated to the introduction of microbes as the main source of antimicrobial drugs, even though some of these secondary metabolites have also other potent biological activities as well. For the antibacterials, different Streptomyces species have been the most productive bacteria. The classical example of an antibiotic discovered as a defense mechanism against another microbe is the discovery of penicillin in the cultures of Penicillum fungi in 1928.

Marine invertebrates as a source for bioactive compounds

Besides terrestrial ecosystems, marine environments are considered potential sources for new bioactive agents. The first breakthroughs in the area were the arabinose nucleosides discovered from marine invertebates in 1950s, demonstrating for the first time that also sugar moieties other than ribose and deoxyribose can yield bioactive nucleoside structures. However, it took as long as 2004 until the first marine-derived drug was approved. The cone snail toxin ziconotide, also known as Prialt, was then approved by Food and Drug Administration (FDA, USA) to treat severe neuropathic pain. Several other marine-derived agents are now in clinical trials for indications such as cancer, anti-inflammatory use and pain. One of the most promising classes of these agents in pipeline are bryostatin-like compounds, that are under investigation as anti-cancer therapy as such and particularly as combination with other cytostatic drugs.^[5]

Chemical diversity of Natural Products

As above mentioned, combinatorial chemistry was a key technology enabling the efficient generation of large screening libraries for the needs of high-throughput screening. However, now, after two decades of combinatorial chemistry, it has been pointed out that despite the increased efficiency in chemical synthesis, no increase in lead or drug candidates has been reached [2]. This has led to analysis of chemical characteristics of combinatorial chemistry products, compared to existing drugs and/or natural products. The chemoinformatics concept chemical diversity, depicted as distribution of compounds in the chemical space based on their physicochemical characteristics, is often used to describe the difference between the combinatorial chemistry libraries and natural products. The synthetic, combinatorial library compounds seem to cover only a limited and quite uniform chemical space, whereas existing drugs and particularly natiral products, exhibit much greater chemical diversity, distributing more evenly to the chemical space. The most prominent differences between natural products and compounds in combinatorial chemistry libraries is the number of chiral centers (much higher in natural compounds), structure rigidity (higher in natural compounds) and number of aromatic moieties (higher in combinatorial chemistry libraries). Other chemical differences between these two groups include the nature of heteroatoms (O and N enriched in natural products, and S and halogen atoms more often present in synthetic compounds), as well as level of non-aromatic unsaturation (higher in natural products). As both structure rigidity and chirality are both well-established factors in medicinal chemistry known to enhance compounds specificity and efficacy as a drug, it has been suggested that natural products compare favourable to today's combinatorial chemistry libraries as potential lead molecules.

Methodologies in natural product drug discovery

Identification of biologically active material

Two main approaches exist for the finding of new bioactive chemical entities from natural sources; either random collection and screening of material, or exploitation of ethnopharmacological knowledge in the selection. The former approach bases itself on the fact that only a very smaal part of globes’s biodiversity has ever been tested for any biological activity, and on the other hand, particularly organisms living in a species-rich environment need to evolve defence and competition mechanism to survive. Thus, collection of plant, animal and microbial samples from rich ecosystems may give rise to isolation of novel biological activities. One example of a successful use of this strategy is the screening for antitumour agents, performed by National Cancer Institute in USA started in 1960s. Cytostate paclitaxel (taxoid) was identidifed during this campaign from Pacific yew tree Taxus brevifolia. Paclitaxel showed anti-tumour activity with previously unknown mechanism (stabilization of microtubules) and is now approved for clinical use for the treatment of lung, breast and ovary cancer, as well as for Kapos sarcoma.

Besides random selection, the selection of starting material may be done by collecting knowledge on use of plants and other natural products as herbal medicines and thereby get an idea of potential biological activities. Ethnobotany, the study of the use of plants in the society, and particularly ethnopharmacology, an area inside ethnobotany focused on mediical use of plants, may therefore provide invaluable information, as illustrated by the example of artemisinin, an antimalarial agent from sweet wormtree Artemisiae annua, used in Chinese medicine since 200 DC and nowadays in use against multiresistant malarial protozoa Plasmodium falsiparum.

Structural elucidation

The elucidation of the chemical structure of the newly identified bioactive agent remained a long time the most time-consuming step in natural product drug discovery. The elucidation of the chemical formula is a critical isuue, to avoid double hits, i.e. identification of a chemical agent that is alreadyknown for its structure and chemical activity. New methods have been applied in this field, thus making the task easier and faster. Particularly mass spectrometry (MS) has contributed largely to the enhanced ease of structure determination. MS is a method in which individual compounds are identified based on their mass/charge ratio, after an artificial ionization. Natural compounds mainly exist as mixtures (when extracted from their origin) so the combination of liquid chromatography and mass spectrometry (LC-MS) is often used to separate the individual compounds and determine their mass/charge ratios online. Databases of mass spectras for known natural compounds are available, allowing the comparisons. Besides MS, also nuclear magnetic resonance (NMR) spectroscopy is an important technique when chemical structures of natural products are to be determined. It yields information of individual hydrogen and carbon atoms in the structure, allowing detailed reconstruction of the molecule’s architecture.

See also

• Drug discovery
• Pharmacognosy
• High-throughput screening
• Natural product

References

1. ^ Koehn FE, Carter GT (2005) The evolving role of natural products in drug discovery. Nat Rev Drug Discov 4: 206-220.
2. ^ Feher, M. and Schmidt, JM. Property Distributions: Differences between Drugs, Natural Products, and Molecules from Combinatorial Chemistry J. Chem. Inf. Comput. Sci., 43 (1), 218 -227, 2003
3. ^ Newman, D and Cragg, G. Natural products as drug over the past 25 years J Nat Prod 70(3): 461-477. (2007).
4. ^ F. von Nussbaum, M. Brands, B. Hinzen, S. Weigand, D. Häbich, Angew. Chem. 2006, 118, 5194–5254; Angew. Chem. Int. Ed. 2006, 45, 5072–5129. Antibacterial Natural Products in Medicinal Chemistry – Exodus or Revival? PMID 16881035
5. ^ Newman, D and Cragg, G. Marine-derived agents in clinical and preclinical trials. J Nat Prod. 2002.