Nature as a Source of Drug Compounds

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Chapter: Medicinal Chemistry : Introduction to Medicinal Chemistry

Despite the rise of combinatorial chemistry as an integral part of lead-discovery process, the natural products still play a major role as starting materials for drug discovery.


Despite the rise of combinatorial chemistry as an integral part of lead-discovery process, the natural products still play a major role as starting materials for drug discovery. A recent study suggested that 974 small molecule new chemical entities were developed in the past 25 years; among these, 63% were natural, derived, or semisynthetic derivatives of natural products. For certain therapy areas, such as antimicrobials, antineoplastics, antihypertensive, and anti-inflammatory drugs, natural products may be useful as a source of novel chemical structures for modern techniques of development.

Plant-Derived Bioactive Materials

Before Paracelsus, vast majority of the traditionally used crude drugs in Western medicine were plantderived extracts. This has resulted in an inherited pool of information of the healing potential of plant species, thus making them an important source of starting materials for drug discovery. A different set of metabolites is sometimes produced in the different anatomical parts of the plant (i.e. roots, leaves, and flowers), and botanical knowledge is crucial also for the correct identification of bioactive plant materials.

Microbial Species with Bioactive Metabolites

Microbes have to compete for living space and nutrients. To survive in these conditions, many microbes have developed abilities to prevent the competing species from proliferation. This phenomenon has led to the microbes being the main source of antimicrobial drugs. Streptomyces species have been a source of antibiotics. The classical example of an antibiotic discovered as a defence mechanism against another microbe is the discovery of penicillin in bacterial cultures contaminated by penicillium fungi in 1928.

Marine Invertebrates as a Source of Bioactive Compounds

Marine environments are potential sources of new bioactive agents. Arabinose nucleosides discovered from marine invertebrates in 1950s, demonstrated that sugar moieties other than ribose and deoxyribose can yield bioactive nucleoside structures. However, it was in 2004, when the first marine-derived drug was approved. The cone snail toxin, ziconotide, also known as Prialt, was 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, inflammation, and pain. One class of these agents are bryostatin-like compounds, under investigation as anticancer agent.

Chemical Diversity of Natural Products

As mentioned earlier, combinatorial chemistry was a key technology enabling the efficient generation of large screening libraries for the needs of HTS. It has been pointed out that, despite the increased efficiency in chemical synthesis, no increase in lead or drug candidates have been reached even after two decades of combinatorial chemistry. This has led to an analysis of the chemical characteristics of combinatorial chemistry products, as compared to the existing drugs and the natural products. The chemoinformatics is a concept of chemical diversity depicted as the distribution of compounds in the chemical space on the basis of their physicochemical characteristics, and is often used to describe the difference between 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, particularly, natural 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 are the number of chiral centres (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; S and halogen atoms more often present in synthetic compounds), as well as level of nonaromatic unsaturation (higher in natural products). As both structure rigidity and chirality are wellestablished factors in medicinal chemistry and are known to enhance compounds specificity and efficacy as a drug, it has been suggested that natural products compare favourably to today’s combinatorial chemistry libraries as potential lead molecules.

Methodologies in Natural Product Drug Discovery 


Random collection or screening of material, or exploitation of ethnopharmacological knowledge in the selection are the main approaches exist for the finding of new bioactive chemical entities from natural sources. The former approach is based on the fact that only a small part of Earth’s biodiversity has ever been tested for biological activity, and organisms living in a species-rich environment need to evolve defence and competition mechanism to survive. A collection of plant, animal, and microbial samples from rich ecosystems might give rise to novel biological activities. One example of a successful use of this strategy is the screening for antitumour agents, by the National Cancer Institute in USA, started in 1960s. Paclitaxel was identified from Pacific yew tree Taxus brevifolia. Paclitaxel showed antitumour activity through a previously undescribed mechanism (stabilization of microtubules), and is now approved for clinical use for the treatment of lung, breast, and ovary cancer, as well as for Kaposi’s sarcoma.

The selection of the starting materials may be done by collecting knowledge about the use of plants and the other natural products as herbal medicines, and thereby getting an idea of their potential biological activities. Ethnobotany, the study of the use of plants in the society, and particularly, ethnopharmacology, an area inside ethnobotany, focused on medicinal use of plants. Artemisinin, an antimalarial agent, from sweetworm tree, Artemisia annua, used in Chinese medicine since 200 BC is one of the drugs used as a part of combination therapy for multiresistant, Plasmodium falciparum.


The elucidation of the chemical structure is critical to avoid double hits (i.e. the identification of a chemical agents that are already known for its structure and chemical activity), and for a long time remained as the most time-consuming step in the natural product drug discovery process. Mass spectrometry (MS) is a method in which individual compounds are identified based on their mass/charge ratio, after ionization and it has contributed to the enhanced ease of structure determination. Chemical compounds exist in nature as mixtures, therefore, the combination of liquid chromatography and mass spectrometry (LC-MS) is often used to separate the individual chemicals. Mass spectral databases for known compounds are available. Apart from MS, nuclear magnetic resonance (NMR) spectroscopy is another important technique for determining chemical structures of natural products. NMR yields information about individual hydrogen and carbon atoms in the structure, allowing detailed reconstruction of the molecule’s architecture.

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