Natural product drug discovery

This article describes the utilizarion 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, the represent complementary strategies for lead identification in drug discovery.

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 mdiated by specific interactions of the drug molecule with biological macromolecules, (proteins or nucleic acids in most cases) led scientist 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 maked 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 cimpiunds 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 19870s, the new drug compounds were almost solely of natural origin. However, as the fiels of snthetic chemistry become 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) 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 21yh century.
 * introduction of high-throughput screening (HTS) as the standard methid 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 firendly format
 * general decline in interest towards developing new antibiotic drugs, a traditional ly strong area of natural product drug discovery.

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. 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 uodate of the report was published in 2007 [2], covering years 1981-2006. Acoordinf to their report, of the 974 samll 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 antihpertensive and anti-inflammatory drugs, the numberw were even higher (for instance, approximately 75% of all approved small molecule new chemical entities were derived from nature.

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 milleniums 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 an 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
Bsides 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 2005 until the first marine-derived drug was approved. The cone snail toxin known as Prialt, was then approved by Food and Drug Administration (FDA, USA) for antimicrobial use.

Chemical diversity of Narueal Products[3]
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 productscompare favourable to today’s combinatorial chemistry libraries as potential lead molecules.

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 knowlegde 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 an 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 isolatopn 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 knoelrdge on use of plants and other natural products asherbal medicines and thereby get an idea of potential biological activities. Even though folk medicine and healers are disaooearing almost completely from Western society and the area is often referred to as alternative medicine, it is worth remembering that a major part og earth’s population still rely on nature-derived drugs as their only medication. 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.