A “paradigm shift” in drug discovery occurred in the early 19th century, marked by the isolation of pure bioactive entities from medicinal plants, beginning with the isoquinoline alkaloid, morphine. The purification of plant drug molecules such as atropine, cocaine, codeine, digitoxin, and quinine, later in the same century, proved to be significant not only for the extensive medicinal uses of these isolates, but also for the crucial roles these molecules played in better understanding human disease and in the development of organic and medicinal chemistry.
In the 20th century, additional important drugs were isolated from plants, including artemisinin, digoxin, paclitaxel, vinblastine, and vincristine. Also in this same century, as a result of advances made in pharmacology and a better understanding of human diseases at the molecular level, physicians and pharmacists gradually shifted from the use of plant extractives in prescriptions to pure naturally occurring and synthetically modified natural products, or totally synthetic compounds. Today, the effort to find new bioactive principles from medicinal plants may bring together scientists working in a diverse range of disciplines including biochemistry, botany, ethnobotany, medicinal chemistry, microbiology, molecular biology, organic chemistry, pharmaceutics, pharmacognosy, pharmacology, plant ecology, and taxonomy. The advances in molecular biology are duly reflected in the complexity of bioassays employed in the medicinal plant drug discovery field, and also provide the “mode of action” information at the molecular level in a rapid and accurate fashion. Preliminary in vitro experiments may then be followed up with a variety of in vivo bioassays.
Terrestrial plants and other organisms are known to be the sources of a plethora of small organic molecules, representing considerable structural diversity, which may not be matched by the creativity of synthetic chemists. When all currently known (both synthetic and natural) chemical entities are taken into consideration, the area of chemical space occupied by bioactive molecules is a relatively limited one. When considered statistically, natural products have been found to account for much greater chemical diversity than compounds generated by both synthetic and combinatorial chemistry methods together. They also possess some unique structural differences, which afford them with greater druglike qualities. Accordingly, libraries of pure natural product, when combined with the advantages of combinatorial chemistry, offer an even more effective and reliable avenue for exploring the “more bioactive part” of chemical space when compared with a purely synthetic approach.
From a chemical informatics perspective, natural products are significantly different from syntheticand combinatorial chemistry-produced compounds in that they have more single bonds, and protonated amino and free hydroxyl groups, while having fewer aromatic rings. Also, natural compounds possess a greater diversity of ring systems and tend to be more rigid than their synthetic counterparts. Natural products also exhibit more chiral centers and fewer rotatable bonds than substances produced by synthesis. The “rule of five,” developed originally to guide the efforts of combinatorial chemistry, has spearheaded a new approach to drug discovery by defining the physicochemical characteristics a “drug-like” molecule should have. In this respect, comparison studies have shown that natural products resemble proprietary drugs and show a high degree of “druglikeness,” compared to their synthetic counterparts. The intricate biosynthetic processes that lead to bioactive secondary metabolites from organisms with bioactivity continue to be a major research interest and there has been much thought as to how and why these compounds are biosynthesized. The most widely accepted and satisfactory explanations refer to an evolutionary perspective.