SERENDIPITOUS DRUG DISCOVERY IN FIELD OF PHARMACY

SERENDIPITOUS DRUG DISCOVERY IN THE FIELD OF PHARMACY

Y. Srikala*, Jyothirmayee, S. Sharadha, V. Uma Maheshwara Rao

C.M.R College of Pharmacy, Kandlakoya (v), Medchal, Hyderabad – 501 401

 

Serendipity is not merely stumbling on things unsought for, it is the ability to see significances and find values in the things stumbled upon. Serendipity means an aptitude for making desirable discoveries by accident. It was found that the discovery of 5.8% (84/1437) of all drugs on the market involved serendipity. Of these drugs, 31 (2.2%) were discovered in the laboratory and 53 (3.7%) were discovered in a clinical setting. In addition, 263 (18.3%) of the pharmaceuticals in clinical use today are chemical derivatives of the drugs discovered with the aid of serendipity. Therefore, in total, 24.1% (347/1437) of marketed drugs can be directly traced to serendipitous events confirming the importance of this elusive phenomenon. In the case of anticancer drugs, 35.2% (31/88) can be attributed to a serendipitous event, which is somewhat larger than for all drugs. Recently a new concept of Known Drug Space (KDS) has been developed to help drug designers to navigate chemical space based on the analysis of drugs in clinical use. It is known that 10% of KDS are unaltered natural products and 29% are their derivatives (semi-synthetics). The therapeutic field that has benefited the most from serendipity is central nervous system active drugs reflecting the difficulty in designing compounds to pass the blood-brain-barrier and the lack of laboratory-based assays for many of the diseases of the mind.

In general, 24% of all pharmaceuticals currently on the market were affected in a positive way during their development by this phenomenon with CNS active drugs being the most prominent. This leads to the conclusion that drug discovery is based on good science and where intuition, critical thinking, sagacity and open-mindedness play crucial roles.

 

INTRODUCTION Serendipity is not merely stumbling on things unsought for, it is the ability to see significances and find values in the things

stumbled upon. Serendipity means an aptitude for making desirable discoveries by accident. Nearly all the great discoveries in chemotherapy have been made as a result of a false hypothesis or due to a so-called chance

observation.

If the frontiers of knowledge is wide open, causes of phenomena mostly hide in the dark, where many scientists deem research

most challenging and exhilarating, chance and serendipity play bigger roles.

We explore the characteristics of a prepared mind in three cases.  In the cases of scientists getting their ideas in dreams, we

examine the cognitive psychology of thinking and problem solving.  The second case we take is one of the most famous

serendipitous drug discoveries, that of penicillin.  Here we examine how the ability and inability to “connect the dots”

facilitated and limited Fleming’s contribution to the development of the antibiotic medicine.  Many people would consider our

third case, drug screening, to be the antithesis of serendipity.  Sure, instead of running into something unintentionally,

screening set out with the intention to find something

STATISTICS: It was found that the discovery of 5.8% (84/1437) of all drugs on the market involved serendipity. Of these drugs, 31 (2.2%)

were discovered in the laboratory and 53 (3.7%) were discovered in a clinical setting. In addition, 263 (18.3%) of the

pharmaceuticals in clinical use today are chemical derivatives of the drugs discovered with the aid of serendipity. Therefore, in

total, 24.1% (347/1437) of marketed drugs can be directly traced to serendipitous events confirming the importance of this

elusive phenomenon. In the case of anticancer drugs, 35.2% (31/88) can be attributed to a serendipitous event, which is

somewhat larger than for all drugs

The distribution of the serendipity types (laboratory-based and clinical) and their chemical derivatives in clinical use (100% = 1437).

SERENDIPITOUS DRUG ACTS ON CARDIOVASCULAR SYSTEM:

During the 1920's, cattle began to mysteriously die from internal hemorrhage. The cause was attributed

generally to spoiled sweet clover, but when the Great Depression hit and ranchers could ill afford to lose a single

cow, one frustrated farmer, Ed Carlson, packed up his dead cow along with a milk can filled with blood that

refused to clot and drove to the Wisconsin Alumni Research Foundation (WARF) looking for answers. There

researcher Karl Link was able to isolate the naturally occurring chemical compound coumarin, which, when

oxidized in damp hay, is the culprit anticoagulant. In 1945, Link came up with the idea to use the compound as a

rodenticide, as it is still used today. Scientists continued to study and test coumarin.

In 1955, it was given to President Dwight Eisenhower after a myocardial infarction and today - from cattle-

killer, to rat-killer, to human life-saver - Warfarin is the most widely used anticoagulant in the world.

Figure 1. The systematization of serendipity.

Schlueter P J , and Peterson R T Circulation 2009;120:255-263

Copyright © American Heart Association

Alexander Fleming didn't clean up his workstation before going on vacation one day in 1928. When he came back, Fleming noticed that there was a strange fungus on some of his cultures. Even stranger was that bacteria didn't seem to thrive near those cultures.Penicillin became the first and is still one of the most widely used antibiotics.

Alexander Fleming didn't clean up his workstation before going on vacation one day in 1928. When he came back, Fleming noticed that there was a strange fungus on some of his cultures. Even stranger was that bacteria didn't seem to thrive near those cultures.Penicillin became the first and is still one of the most widely used antibiotics.

SERENDIPITOUS ANTIBIOTIC DRUG:

Alexander Fleming didn't clean up his workstation before going on vacation one day in 1928. When he came

back, Fleming noticed that there was a strange fungus on some of his cultures. Even stranger was that bacteria

didn't seem to thrive near those cultures.

Penicillin became the first and is still one of the most widely used antibiotics.

In 1928, Scottish Scientist Sir Alexander Fleming was studying Staphylococcus – the bacteria that causes food

poisoning.

He turned up at work one day and discovered

a blue-green mould that seemed to be inhibiting growth of the bacteria. He grew a pure culture of the mould and

discovered

that it was a Penicillium mould.

SERENDIPITOUS ANTI DIABETIC DRUG:

Often several serendipitous discoveries contribute to the establishment of a major therapy. 

Take for example insulin for diabetes.  Chance observation of flies attracted to the sugar-rich urine of

experimental dogs with pancreas removed led to the discovery that the pancreas is causally related to

diabetes. 

Since that discovery in 1889, many scientists tried to extract the pancreas’ secretion and use it as a

remedy for diabetes.  Some almost made it; others failed, but not necessarily because they were more

ignorant. 

When Frederick Banting, Charles Best, and John Macleod succeeded to extract insulin and demonstrate

its therapeutic efficacy in 1921, they designed their crucial experiment on a wrong conception

SERENDIPITOUS ANTICANCER DRUG:

Nearly all the great discoveries in chemotherapy have been made as a result of a false hypothesis or due

to a so-called chance observation.

Chemotherapy involves the use of low-molecular-weight drugs to selectively destroy a tumor or at least

limit its growth.

Nitrogen mustards were the first agents to be used clinically; their use resulted from the accidental

discovery that the mustard gas used in world war II had antileukemic properties. Since then, important

advances have been made in the development of new anticancer drugs. For example, cisplatin, which was

also discovered serendipitously, provided a major advance in the treatment of testicular and ovarian

carcinomas.

The discovery of cis-platin was serendipitous. In 1965, Rosenberg was looking into the effects of an electric field on the

growth of Escherichia coli bacteria. He noticed that bacteria ceased to divide when placed in an electric field but what

Rosenberg also observed was a 300-fold increase in the size of the bacteria.

He attributed this to the fact that somehow the platinum-conducting plates were inducing cell growth but inhibiting cell

division. It was later deduced that the platinum species responsible for this was cis-platin.

Rosenberg hypothesized that if cis-platin could inhibit bacterial cell division it could also stop tumor cell growth. This

conjecture has proven correct and has led to the introduction of cis-platin in cancer therapy. Indeed, in 1978, six years after

clinical trials conducted by the NCI and Bristol-Myers-Squibb, the U.S. Food and Drug Administration (FDA) approved cis-

platin under the name of Platinol for treating patients with metastatic testicular or ovarian cancer in combination with other

drugs but also for treating bladder cancer. 

Cisplatin is a chemotherapy drug commonly prescribed to lung cancer patients. Because it is administered systemically, the

entire body gets a hefty dose of the toxic substance with side effects that are often quite debilitating. To better target the drug

toward lung CA, researchers at the University of Strachlyde, Glasgow and TRANSAVE (Monmouth Junction, NJ) have

independently developed inhalation microcapsules that can contain cisplatin.

SERENDIPITOUS ANTIRHEUMATIC DRUG:

In 1996 we found by serendipity that 2 patients with rheumatoid arthritis (RA) who were taking clarithromycin (CM) to

eradicate Helicobacter pylori experienced a regression of their RA symptoms.

SERENDIPITOUS DRUG USED IN MYOCARDIAL INFARCTION:

A serendipitous discovery by William Smith Tillett in 1933, followed by many years of work with his student Sol Sherry, laid a

sound foundation for the use of streptokinase as a thrombolytic agent in the treatment of acute myocardial infarction.

The drug found initial clinical application in combating fibrinous pleural exudates, hemothorax, and tuberculous meningitis.

In 1958, Sherry and others started using streptokinase in patients with acute myocardial infarction and changed the focus of

treatment from palliation to “cure.”

CURRENT STATUS OF SERENDIPITY

Several putative “anti-serendipity” factors that may interfere with current drug development have

been identified. These include 1) movement toward rational drug design based on translational

research, 2) reduction in the amount of time that clinicians have to observe patients, and 3)

reliance on the double-blind placebo control design to demonstrate efficacy..

The trend toward rational drug design is clear .However, its relationship to serendipity is opaque.

Rational drug design guided by translational research refers to the development of drugs

deliberately designed to alter processes that have been implicated in mental pathology by basic

research

Another putative “anti-serendipity” factor is a constriction in the amount of time that clinical

researchers have to observe drug effects. Interestingly, this has been linked to the closing of long-

term care mental hospitals (i.e., deinstitutionalization)

Another putative “anti-serendipity” factor is the use of the double blind placebo control design . The

principal objection to this design is that the design does not allow for analysis of individual

differences in drug response.

The therapeutic field that has benefited the most from serendipity is central nervous system active

drugs reflecting the difficulty in designing compounds to pass the blood-brain-barrier and the lack

of laboratory-based assays for many of the diseases of the mind.

CONCLUSION:

In general, 24% of all pharmaceuticals currently on the market were affected in a positive way

during their development by this phenomenon with CNS active drugs being the most prominent.

This leads to the conclusion that drug discovery is based on good science and where intuition,

critical thinking, sagacity and open-mindedness play crucial roles.

THANK YOU