Rational of Traditional drug design methods followed in drug discovery

1. method's followed in TRADITIONAL DRUG DESIGN
Naveen K L
M Pharma (2nd Sem)
Dept. of Pharmacology
Srinivas college of Pharmacy
Valachil , Mangaluru

2. Contents
• Introduction
• Evolution of drug discovery
• Traditional Drug Design
• Traditional Drug Design Cycle
• Methods Followed in TDD
• Reference

3. Introduction:
• Drug design is the inventive process of finding new medications based on
the knowledge of the biological target.
• In the most basic sense, drug design involves design of small molecules
that are complementary in shape and charge to the bio molecular target to
which they interact and therefore will bind to it.
• Drug design frequently but not necessarily relies on computer modelling
techniques, this type of modelling is often referred to as computer aided
drug design

4. • Modelling techniques for prediction of binding affinity are reasonably
successful.
• However there are many other properties such as bioavailability,
metabolic half life, lack of side effects etc. that first must be optimized
before a ligand can become a safe and efficacious drug.
• These other characteristic are often difficulties to optimize using
rational drug design technique.

5. Traditional Drug Design:
• Traditional drug discovery involves the origin of drug discovery that
evolved in natural sources, accidental events.
• It was not targeted based and not much systemised today.
• Improved and advancement In pharmaceutical sciences and technology
made it evolutionised to much more systemize modern drug discovery.
• Traditional methods of drug discovery (known as forward Pharmacology),
which rely on trail and error testing of chemical substance on cultured
cells or animals, and matching the apparent effects to treatments .

6. Lead generation:
Natural ligand/ Screening
Synthesis of New Compound by
Molecular Modification of leads
Biological Testing
If Promising
Pre-Clinical
Studies
Drug Design Cycle

7. Major Events In Traditional Drug Discovery
Some relevant milestones could be considered to be:
• 17th century: Anton Van Leeuwenhoek bacteria identified by
microscope.
• 19th century: Louis Pasteur made link between bacteria and
disease.
• 19th century: Robert Koch identified microorganisms for
tuberculosis, cholera and typhoid.
• 1867: Joseph Lister a proponent of the ‘’Germ theory of disease’’
Edinburgh surgeon successfully used carbolic soap (containing phenol) to
prevent infections during surgery.
• 1891: Paul Ehrlich coined the term chemotherapy, used synthetic
chemicals to cure disease.

8. Contribution to Paul
Ehrlich
• The Paul ehrlich is called as ‘ father of modern chemotherapy’.
• original proponent of the ‘’ Magic bullets’’ he aimed to use chemicals
to treat disease.
• In 1910 first fully synthetic drug was made ‘ Salvarsan’ contained
arsenic.
• It was not very good against bacteria but used for treating sleeping
sickness (trypanosomiasis) and syphilis (spirochete disease caused by
treponema pallidium)

9. Methods for Traditional Drug Design:
Random Screening
Trail and Error Methods
Ethnopharmacology
Approach
Serendipity Method
Classical Pharmacology

10. 1.Random Screening:
• It includes random screening of synthetic compounds or chemicals or
natural products by bioassay procedures.
• It involves 2 approaches:
a. Screening of selected class of compounds like alkaloids, flavonoids etc.
b. Screening of randomly selected plants for selected bioassays.

11. Contribution of Random Screening:
• CDRI (Central drug research institute), R and D Organisation of CSIR
(Council of Scientific and Industrial research of India), followed this
approach 3 decades ago
• They screened almost 2000 plants for biological efficacy.
• However, the screening didn’t yield any new drug.
• NCI (National Cancer Institute), NIH (National Institute of Health), USA,
studied 35000 plants species for anticancer activity, spending over two
decades from 1960-1980.

12. Dedicated Random Screening
• Dedicated random screening is like natural product screening except that
known, single compound are tested at random in your biological
assay/screen. It was in this fashion that Gerhard Domagk (IG
Farbenindustrie, Germany, 1931) screened azo dyes (from the paint in
which he worked) in the search for compounds with biological activity.
This led to discovery of the first truly effective sulphonamide
antibacterial Prontosil (a red dye) in 1935.

13. 2.Trail and Error Method
• Trail and error includes berries, roots, leaves and barks that could be
used for medicinal purposes to alleviate symptoms of illness.
 Example:
• Cinchona Bark contains quinine used to reduce fever in malaria.
• Leaves of Azadirachta indica (Neem) are used as anti-inflammatory
and anti-bacterial properties etc.
• Liquorice roots are traditionally used to treat stomach ulcers,
bronchitis and sore throats.
• Willow bark contain salicin----- fever reducing agent.

14. 3.Ethnopharmacology Approach
• Ethnopharmacology is the study of medicinal plants used in specific cultural
group.
• It involves the observation, description and experimental investigation of
indigenous drugs.
• It based on botany, chemistry, biochemistry, pharmacology and many other
disciplines like anthropology, archaeology and history.
Andrographis Paniculata (Kalmegh) was used for dysentery in ethomedicine
and the compound responsible for the activity were found to be
andrographolides.
Morphine from Papaver Somniferum.
Berberine from Berberis aristata.

15. Contribution of Ethnopharmacology
• Discovery of
1.Artemisinin from Artemisia alba for malaria
2.Guggul sterone from commiphora mukul for hyperlipidaemia
3.Boswellic acid from boswellia serrata as a anti-inflammatory
4.Bacosides from bacopa monnieri as nootropic and memory enhancement
was based on leads from these codified system of medicine prevailing in china
and India.

16. 4.Serendipity Method
• ‘’Serendipity’’ refers to ‘an accidental discovery’ i.e. Finding one thing
which looking for something else.
• The most important example of this method is the discovery of
Penicillin by Alexander Fleming in 1928 while doing research on
influenza.
• One more example is the discovery of Cisplatin (used in bladder
cancer) while studying E.coli bacteria.

17. 5.Classical Pharmacology
• Also known as Function based approach.
• Without prior identification of drug target.
• Anciently, drug discovery processes were often based on measuring a
complex response in-vivo such as
 Prevention of experimentally induced seizures.
 Lowering of blood sugar.
 Suppression of inflammatory response.
Eg: Discovery of Foxglove in Europe

18. COMPOUNDS ORIGIN USES
Artemisinin Sweet wormwood Antimalarial
Acyclovir Synthetic analogue of
cytarabine from a marine
source
Used to treat herpes infection
Cyclosporine Fungus Used to prevent tissue graft rejection
Digoxin Foxglove Effective drug for heart failure
Etoposide May apple Synthetic analogue of Phodophylotoxin. Used in
chemotherapy to treat testicular and lung cancer
Vinblastine and
vincristine
Periwinkle Used to treat leukaemia and lymphomas
Pethidine Synthetic analogue of
atropine
Morphine like analgesic

19. Reference:
• European Journal of Pharmacology, ‘’Rational and Traditional Drug
Design’’, Soma Mandal,625(2009); 90-100.