04.01 Preclinical Drug Discovery

Preclinical drug discovery is the process before clinical testing of drugs. The first step in preclinical drug development is the discovery or synthesis of a new drug. At least, 10,000 new molecules are discovered/synthesized for each successful new drug introduced. Extensive preclinical safety and efficacy testing of new drugs are required in animals, and this takes an average of 1.5-3 years.

There are three main ways in which new drugs are derived; chemical modification, rationale drug design, and random screening (Figure 4.2). Serendipity (accidental discovery of something fortunate) may also have a role in drug development.

Figure 4.2 Three methods of drug discovery (Copyright QUT, Sheila Doggrell)

An important group of drugs that were made by chemical modification were the diuretics. However, the initial step was serendipity; an observant physician noticed that sulfanilamide (antibiotic) caused a sodium bicarbonate diuresis the loss of sodium, bicarbonate and water from the kidney. Thus, it was reasoned that a sulphanilamide-like drug could be made that promoted water loss from the body. After a string of chemical modification, chlorothiazide was synthesised. Chlorothiazide increases sodium chloride and water excretion. Further modification of the structure of chlorothiazide led to the discovery of frusemide, which is a very potent diuretic. The thiazide diuretics, such as chlorothiazide, and frusemide are commonly used in the treatment of hypertension and heart failure to promote water loss.

The second method for drug discovery is rationale drug design, and we will consider a new example of this (zanamivir – Relenza).

Rationale drug design usually includes computer design, which is known as in silico. A computer model is made of the site that you want the drug to bind to, and then of the drug with best fit for binding. Then the chemical is synthesised, and then tested pharmacologically to determine, whether the chemicals do as predicted. A drug that was developed in this way is zamanivir (Relenza). Zamanivir can prevent or shorten the flu, which is a virus. Neuramidinase is an enzyme involved in viral replication, and the structure of this enzyme has been determined. The structure shows a pocket, where we may be able to get a drug in to inhibit the enzyme. Zamanivir binds in the pocket to inhibit the activity of neuramidinase, and consequently the replication of the flu virus.

A third approach to drug discovery is random screening. This uses high-throughput screening managed by robotics. There is random screening for biological activity. The screening can be of banks of previously discovered chemical entities, a large number of natural products, and libraries of peptides and nucleic acids. Random screening led to the discovery of the immunosuppressant cyclosporine.