Drug Discovery and Design a Historical Outline

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Chapter: Medicinal Chemistry : Introduction to Medicinal Chemistry

Many years ago peoples used a wide range of natural products for medicinal purpose.


Many years ago peoples used a wide range of natural products for medicinal purpose. These products obtained from animals, vegetables and mineral sources were sometimes very effective. But, many of the products were found to be toxic and it is interesting note that the Greeks used the same word pharmakon for both poisons and medicinal products. Literatures about the ancient remedies was not readily available for use until the invention of the printing press in the 15th century.

In the 19th century, extraction procedures and pure isolated entities (i.e. pure form of substances, such as alkaloids, carbohydrates, etc.) were reported to be in existence. Some of the isolated compounds were proved to be satisfactory as therapeutic agents. The majority of the plant or natural products were believed to be too toxic, such as morphine and cocaine, which was extensively prescribed by physicians.

In the search of finding less toxic medicines than these, on the basis of natural sources, resulted in the introduction of synthetic substances such as drugs in the late 19th century. These improvements were based on the structures of the known biologically active compounds, now referred to as ‘leads’. By adopting this approach, structurally related compounds were developed for the targeted activity. These leadrelated compounds are referred to as analogues.

In 1910, Paul Ehrlich and Saccachiro Hata synthesized the first synthetic drug, Arsphenamine, by combining synthesis with reliable biological screening and evaluation procedures. At the beginning of 19th century, Ehrlich recognized the fact that expected biological and toxic properties of drugs were important in their screening. He demonstrated that the more effective drugs showed a greater selectivity for target microorganism than its host. Consequently, to compare the effectiveness of different compounds, he expressed drug selectivity by a term known as chemotherapeutic index, which he defined as follows:

Chemotherapeutic index = Minimum effective dose/maximum tolerable dose 

On the basis of this concept, over 600 structurally related arsenic compounds were tested and catalogued in terms of the therapeutic index by Paul and Hata. This has led to the discovery of Arsphenamine (Salvarsan, Hoechst, German) in 1909, that could cure mice infected with syphilis. This drug was found to be effective in humans, but it must be used with extreme care, as it is very toxic. However, it was replaced by penicillin in mid-1940s.

Ehrlich’s method of approach is still one of the basic techniques used to design and evaluate new drugs in medicinal chemistry. Recently, chemotherapeutic index has been updated to take into account the variability of individuals, and is now defined as its reciprocal, therapeutic index or ratio.

Therapeutic index = LD50/ED50

where LD50 is the lethal dose that is required to kill 50% of the test animals or microorganisms, and ED50 is the effective dose that is required to produce a therapeutic response in 50% of the test animals or microorganisms. However, the therapeutic index values can only be used as a limited guide of relative usefulness for the different compounds.

Apart from this, serendipity has played a large part in the discovery of drugs. For example, the development of penicillin by Florey and Chain was possible only because of Alexander Fleming, who noted the inhibition of Staphylococcus by Penicillium notatum. Despite our increased knowledge base, it is still necessary to pick a correct starting point for an investigation, if a successful outcome is to be achieved. However, modern techniques, such as computerized molecular modelling and combinatorial chemistry introduced in 1970s and 1990s, respectively, are likely to reduce the number of intuitive discoveries.

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