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The Balance Between Natural Design and Rational Design in Drug Discovery

Fettah Erdogan

posted May 11, 2018

Medicinal products from plants, animals and microorganisms have been, since ancient human civilisation, the main sources of drugs. Natural products are regarded as optimized drug-like molecules and remain the best sources of drugs and drug leads (1). They are known to possess enormous structural and chemical diversity that is unmatched by any synthetic library of small molecules, including those synthesized with newer methodologies (2). The history of medicine is full of remarkable stories of how the discovery of a natural product profoundly impacted advances in biology and inspired drug discovery and therapy, such as the discovery of penicillin and streptomycin. 

An assessment of FDA-approved drugs reveals that approximately 40% of all medicines are either natural products or their derivatives. However, in the context of overall increases in annual FDA approvals (both natural and synthetic drugs), the relative number of natural product-based approvals decreased from 50% (in the 1970s) to 24% (2011-2013) of total annual approvals. (3) Reduction or in-part abandonment of natural product programs by pharmaceutical companies in the late 20th century was mainly due to phenomenal advances in both high-throughput screening (HTS) and combinatorial drug synthesis, generating enormous synthetic libraries of small molecules. Natural product libraries (NPLs), on the contrary, often consist of extracts and partially purified fractions. Due to their structural complexity and relatively low concentrations, the structures of compounds in these extracts are often unclear, resulting in poor compatibility with contemporary HTS platforms (4–6). Moreover, although NPL extracts usually possess numerous bioactive compounds, a compound on its own usually possesses insufficient levels of efficacy. As a result, further pursuit of compounds from NPL is rather limited (7).

It has been shown that the low efficacy of a single compound from natural extracts is mainly due to low concentrations of the compound (8). Normalization of the concentrations of these “hidden” compounds in a natural product extract can be achieved using simple methods (8) to uncover their true bioactivity. Using rational design, compounds with promising effects can be modified to improve their potency and bioavailability. Furthermore, given that natural products often accomplish their therapeutic effect via multi-component interaction (synergistically, additively or antagonistically) rather than the infamous single-protein-targeted approach, the low efficacy of individual compounds analyzed from a natural product extract is not surprising (9). This drug-drug compatibility, which refers to mutual relationship between drugs has been, to some degree, disregarded during the modern screening processes. There is growing evidence indicating that the treatment of complex diseases, such as cancer, using multi-component treatment to trigger or target multiple pathways in the body can have better therapeutic effects in comparison to use of a single-protein-targeted treatment (10–12). This “life lesson” of combination effect from natural medicine, if translated, may decrease side-effects of synthetic medicine. This is because, while increasing drugging efficacy, combined administration of multiple drugs into the body allows for decreased dosage of each individual compound, rendering it more dilute in the blood. This comprehensive approach of using natural precursors in drug discovery and administering lead compounds in a combined manner will, in essence, intuitively decrease non-target effects of potentially “foreign” compounds on the body. The use of natural compounds as precursors, additionally, will help reduce the financial burden resulting from multi-step synthesis of drugs from their basic chemical components. 

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