Serendipity,Random Screening and Molecular Modification

Drug discovery cycle

Drug discovery cycle

Drugs find their way into therapeutics mainly by one of the following routes: serendipity, random screening, extraction of active principles from natural sources, molecular modification of known drugs, selection or synthesis of soft drugs, and rational design. 


Some drugs or novel uses known drugs were discovered by accident in the laboratory or clinic by pharmacists, chemists, physicians, and other investigators. It was alert observations that led, for example, to the introduction in medical practice of acetanilid and phenylbutazone as antipyretics, penicillin as an antibacterial, disulfiram for the treatment of chronic alcoholism, piperazine as an anthelmintic, imipramine and monoamine oxidase inhibitors such as iproniazid as antidepressants, chlorothiazide as a diuretic, mecamylamine as the first hypotensive drug of a novel group. 

Antipyretic properties of acetanilid, now obsolete because of its high toxicity, were discovered by two Strasbourg physicians, Cahn and Hepp, in 1886 when an error was made in a pharmacy that filled their prescription: instead of the prescribed naphthalene, the patient treated for intestinal parasites received acetanilid and this drug caused a decrease in his elevated temperature. The antibacterial action of penicillin was first noted by Fleming in 1929 in a culture of bacteria that was contaminated by a fungus. The anthelmintic action of piperazine was first discovered by Boismare, who used it before 1949 for the treatment of gout. 

Random Screening

In this approach to discover new drugs, all available chemical substances are submitted to a variety of biological tests in the hope that some may show useful activity. As an essentially empirical method, this way of finding new drugs is not very rewarding.  It is estimated that for a new anticonvulsant to emerge through this process, it might be necessary to screen 500000 chemical compounds. A variation of this approach is rationally directed random screening. It was used during World War II to discover new antimalarial; from over 14000 compounds and chemical products prepared and tested by several institutions in 11 countries, just a few were selected for clinical trials. 

Another example of rationally directed random screening is the isolation and identification of products of drug metabolism. It is seen that several drugs are themselves inactive, but they owe their action to their metabolites. Such is the case, for example, with acetanilid and acetophenetidin: these two long-known drugs are metabolized to acetaminophen, which exerts the main analgetic action. For this reason, acetaminophen itself was introduced into therapeutics  

Extraction from Natural Sources

For centuries, humankind has used extracts from plant sources or animal organs for the treatment of various diseases. Several drugs used today, especially antibiotics, vitamins, and hormones, resulted from purification of such extracts and isolation and identification of their active principles. Roughly onefourth of all prescription drugs in developed countries contain active ingredients extracted from plants (morphine, atropine, scopolamine, pilocarpine, etc).  

Molecular Modification

This method of obtaining new drugs, also called molecular manipulation, method of variation, mechanistic method, selective process or approach, is the most used and, as of the present, it is the most productive of new drugs. Molecular modification is a natural development of organic chemistry. Basically, it consists of taking a well-established chemical substance of known biological activity as a lead or prototype and then synthesizing and testing its structural congeners, homologes, or analogs.

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