Drug Discovery: is a process by which a drug candidate is identified and partially validated for treatment of specific disease. Mechanism of action Target identification/ validation Lead identification / optimization ADMET PK/PD It is a programmed process by which drug is discovered and designed It is an intense lengthy process. That means to bring out a drug from discovery to market , a pharmaceutical company requires 10 -15 years and upto 600-800 million dollars. Modeling 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 characteristics are often difficult to optimize using rational drug design techniques. Traditional drug design: Traditional drug discovery involves the origin of drug discovery that is evolved from natural sources, acciuta events. It was not target based and not much systemised as today Improved and advancements in pharmaceutical science and technology made it evolutionised to much more systemize modern drug discovery Traditional methods of drug discovery (known as forward pharmacology), which rely on trial-and-error testing of chemical substances on cultured cells or animals, and matching the apparent effects to treatments Methods of Traditional drug design: 1.Random screening 2.Trial and error method 3.Ethnopharmacology approach 4.Serendipity method Classical pharmacology Chemical structure based drug discovery. Random screening:It includes random screening of synthetic compounds or chemicals or on natural products by bioassay procedures. Involves two approaches: 1.Screening for selected class of compounds like alkaloids, flavonoids, etc 2. Screening of randomly selected plants for selected bioassays Dedicated Random Screening: Dedicated random screening is like natural product screening except that known. single compounds 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 factory in which he worked) in the search for compounds with biological activity. This led to the discovery of the first truly effective sulphonamide antibacterial Prontosil (a red dye) in 1935 Contribution of Random screening; Later, the National Cancer Institute (NCI) of National Institute of Health, USA, studied about 35,000 plant species for anticancer activity, spending over two decades from 1960 to 1980. It resulted in proving two success stories, which were those of paclitaxel and camptothecin Trial n error method: Trial and error method includes berries, roots, leaves and barks could be used for medicinal purposes to alleviate symptoms of illness. Examples: Willow bark -contains salicin -fever reducing in general Cinchona bark - contains quinine – fever associated with malaria Chinese

1. DRUG DISCOVERY
Presented by-
Aadya Raj Pandey
M.Pharm (pharmacology)
2NDsemester
Presented to-
Dr. Brijes Kumar
Department of Pharmacology
BBAU Lucknow
TRADITIONAL VS RATIONAL DRUG DESIGN..
(A CENTRAL UNIVERSITY)
ACCREDITED ‘A++' GRADE BY NAAC 2023 (IN FIRST CYCLE)
ISO 14001:2015

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What will you learn after
this presentation…??

3. Content
 Disease
 Drug
 Drug discovery
 Drug design
 Various approaches to drug design
 Introduction to Traditional drug design
 Types of traditional drug design
 Concept of Rational drug design
 Types of rational drug design
 Structure based drug design
 Ligand based drug design
 Pharmacophore drug design
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✓ Disease:
• A disorder of structure or function in human,
animal or plant specially one that specific
symptoms, or that affects a specific location.
• It is not simply a result of direct physical injury.

5. Drug:
The chemical substances (in raw form) which affects
the mind or body which is used in:
✓ Dignosis
✓ Prevention
✓ Treatment
Of disease or other abnormal condition.
Medicine:
Any drug which is developed through any process and
convert into dosage form (S/L/G) then it is called
medicine.
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6. Introduction
Drug Discovery: is a process by which a drug
candidate is identified and partially validated for
treatment of specific disease.
 Mechanism of action
 Target identification/ validation
 Lead identification / optimization
 ADMET
 PK/PD
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7. ….
✓ It is a programmed process by which
drug is discovered and designed
✓ It is an intense lengthy process.
✓ That means to bring out a drug from
discovery to market , a
pharmaceutical company requires 10 -
15 years and upto 600-800 million
dollars.
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9. Facts about drug
discovery& development
1 time 10-15 years
2 cost 1 billion$
3 Drugs tested 5000-10000
4 Subjects tested 1000- 5000
5 Approved drug 1

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Drug discover
y and
development
Preclinical
research
Clinical
development
FDA review
Post market
monitoring
Figure : steps involved in drug development.

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DRUG DESIGN:
 Drug design is the inventive process of finding new
medications based on the knowledge of the
biological target.
 The most fundamental goal in drug design is to predict
whether a given molecule will bind to a target and if so
how strongly
 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 modeling techniques. This type of
modeling is often referred to as computer-aided drug
design.

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✓ Modeling 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 characteristics are often
difficult to optimize using rational drug
design techniques.

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✓ Traditional drug design:
 Traditional drug discovery involves the origin of drug discovery
that is evolved from natural sources, acciuta events.
 It was not target based and not much systemised as today
 Improved and advancements in pharmaceutical science and
technology made it evolutionised to much more systemize
modern drug discovery
 Traditional methods of drug discovery (known as forward
pharmacology), which rely on trial-and-error testing of chemical
substances on cultured cells or animals, and matching the
apparent effects to treatments

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Difference between Traditional and Rational drug
delivery:
Traditional Rational
1. Based on classical pharmacology,
2. Phenotypic screening (PDD)
3. Forward pharmacology
1. Reverse pharmacology
2. Target based drug delivery(TBDS)
Compounds are screened in cellular or
animal models of disease to identify
compounds that cause a desirable change
in phenotype.
that is, working from the target backward to
identify new drugs starting with screening
libraries of compounds for affinity for
particular target.
After the lead discovery, efforts are made
for biological target.
The hits from these screens are then used as
starting points for drug discovery
Eg: This method became popular after
the sequencing of the human genome which
allowed rapid cloning and synthesis of large
quantities of purified proteins.

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16.  Random screening
 Trial and error method
 Ethnopharmacology approach
 Serendipity method
 Classical pharmacology
 Chemical structure based drug discovery
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Methods of Traditional drug design:

17. Random screening:
It includes random screening of synthetic compounds or
chemicals or on natural products by bioassay
procedures. Involves two approaches:
1.Screening for selected class of compounds like
alkaloids, flavonoids, etc
2. Screening of randomly selected plants for selected
bioassays
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Dedicated Random Screening:
 Dedicated random screening is like natural product screening
except that known. single compounds 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 factory in which he worked) in the search for
compounds with biological activity.
 This led to the discovery of the first truly effective
sulphonamide antibacterial Prontosil (a red dye) in 1935.

19. Contribution of Random screening
✓ Later, the National Cancer Institute (NCI) of National
Institute of Health, USA, studied about 35,000 plant
species for anticancer activity, spending over two
decades from 1960 to 1980.
✓ It resulted in proving two success stories, which were
those of paclitaxel and camptothecin.
19

20. Trial n error method
Trial and error method includes berries, roots, leaves and
barks could be used for medicinal purposes to alleviate
symptoms of illness.
Examples:
✓ Willow bark -contains salicin -fever reducing in general
✓ Cinchona bark - contains quinine – fever associated
with malaria
✓ Chinese herbal remedies - used to treat many illness.
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Ethnopharmacology approach-
• Depends on empirical experiences related to the use of botanical
drugs for the discovery of biologically active New Chemical
Entity.
• This process involves the observation, description, and
experimental investigation of indigenous drugs.
• It is based on botany, chemistry, biochemistry, pharmacology,
and many other disciplines like anthropology, archaeology,
history, and linguisticsIn history several examples are present.
• Andrographis paniculata was used for dysentery in
ethnomedicine and the compounds responsible for the activity
were isolated as andrographolide.
• Morphine from Papaver somniferum,
• Berberine from Berberis aristata,
• •Picroside from Picrorrhiza kurroa

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Contribution of Ethnopharmacological approach:
 Discovery of artemisinin from Artemesia alba for malaria,
 guggul sterones from Commiphora mukul (for hyperlipidemia),
 boswellic acids from Boswellia serrata (anti- inflammatory)
 bacosides from Bacopa monnieri (nootropic and memory
enhancement) was based on the leads from these codified systems of
medicine prevailing in China and India.

23. Serendipity method :
"Serendipity" refers to "an accidental discovery;" i.e,
"finding one thing while looking for something else No
scientific discovery has ever been made by pure luck.
-All happy accidents in science have one point in
common: "each was recognized, evaluated and acted upon
in the light of the discoverer's total intellectual
experience.“
-The serendipitous discovery of penicillin in 1928 by
Alexander Fleming occurs. Fleming was engaged in
research on influenza when one of his staphylococcus
culture plates had become contaminated and developed a,
mold that created a, bacteria
-free circle Fleming recognized the possible significance
of the bacteria
-free circle and by isolating the mold in pure culture
Serendipity method

24. ✓ He found that it, produced a substance that has a
powerful destructive effect on many of the common
bacteria that infect man.
✓ He named the antibacterial substance liberated into
the fluid in which the mold was grown "penicillin" after
Penicillium notatum, the contaminant of the
staphylococcus colony that led to the discovery.
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25. ✓ Also known as function based approach.
✓ Anciently, drug discovery programmes were often
based-successfully-on measuring a complex response
in vivo.
✓ Such as prevention of experimentally induced seizures,
lowering of blood sugar, or suppression of an
inflammatory response.
✓ Without the prior identification of a drug target
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Classical pharmacology

26. ✓ Examples of function based drug discovery
✓ Usually natruarally derived sources of drugs
comes in this approach
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ANCIENT
GREECE
AMERICA CHINA EUROPE
OPIUM
(opium
somniferum)
CINCHONA
BARK
MA HUANG ERGOT
BELLADONA
(atropa
belladonna)
COCA LEAVES
(Erythroxylon)
FOXGLOVE
(Digitalis)

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Format & content of NDA
COMPOUND ORIGIN USES
Artemisinin Sweet warmwood Antimalarial derived from
Chinese medicine
acyclovir Synthetic analogue
of cytarabine from
marine sources
Used to treat herps
infection
cyclosporin fungus Used to prevent tissue graft
infection.
digoxin foxglove Digitalis has been used for
heart failure
disogenin Mexican wild yam Used in manufacture of
steroidal contraceptives
and hormone replacement
therepy
etiposide May Apple Synthetic analogue of
podophyllotoxin, used to
treat
Vincristine
vinblastine
periwinkle Used to treat leukemias
and lymphomas

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RATIONAL DRUG DESIGN

29. Rational drug design
✓ Rational drug design is also sometimes referred as Drug
design or Rational design. It is a process in which finding of
new medication based on knowledge of biological target is
done. It involves design of small molecules that are
complementary in shape and charge to bimolecular target.
✓ The drug is most commonly an organic small molecule that
activates or inhibits the function of a bio molecule such as a
protein, which in turn results in a therapeutic benefit to the
patient. In contrast to traditional methods of drug discovery,
which rely on trial-and-error testing of chemical substances
on cultured cells or animals, and matching the apparent
effects to treatments, rational drug design begins with a
hypothesis that modulation of a specific biological target may
have therapeutic value.
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Rational Drug Design; Example - Cimetadine
(Tagamet)
Starts with a validated biological target and ends up with a drug that optimally interacts with
the target and triggers the desired biological action.
Problem: histamine triggers release of stomach acid. Want a histamine antagonist to prevent
stomach acid release by histamine = VALIDATED BIOLOGICAL TARGET.
Histamine analogs were synthesized with systematically varied structures (chemical
modification), and SCREENED. N-guanyl- histamine showed some antagonist properties =
LEAD compound.

31. RATIONAL DRUG DESIGN
Rational drug design is a process in drug discovery that
involves designing and developing new medications based
on the understanding of the target disease and the
molecular interactions between the drug and its target.
It aims to optimize the therapeutic efficacy and minimize
side effects by designing molecules that interact with
specific target sites in the body.
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✓ Rational drug design takes a more targeted and
systematic approach by utilizing information of the
target structure and function, as well as molecular
modeling and computational techniques, to design
molecules that specifically interact with the target of
interest.
✓ This approach allows researchers to focus on specific
molecular targets involved in disease processes,
increasing the likelihood of developing effective drugs

33. ✓ ……
The process of rational drug design typically involves the following steps:
a) Target identification and validation
b) Target characterization
c) Virtual screening and molecular modeling
d) Lead compound identification(heart of drug design)
e) Lead optimization
f) Preclinical and clinical testing
g) Drug approval and post-marketing surveillance.

34. ✓ Methods for Rational drug design:
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Ligand based
drug designing
QSAR
Pharmacophore
perception
Structure
based drug
design
Docking
De novo drug
design

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LIGAND BASED DRUG DESIGN:
• It relies on the other molecules that bind to the biological target of
interest.
• In other words, a model of the biological target may be built based on
the knowledge of what binds to it and this model in turn may be used to
design new molecules.
• In QSAR, biological activity is determined from the physico-chemical
properties of drug. So these QSAR relationships in turn used in the
prediction of biological activity of new analogues.
Biological Activity = f (Physico-chemical properties)

36. STRUCTURE BASED DRUG DESIGN
✓ It relies on the knowledge of 3D structure of the
biological target.
✓ 3D Structure is obtained by either X-Ray
crystallography or NMR spectroscopy.
✓ Using the structure of receptor, candidate drugs
that are predicted to bind with high affinity and
selectivity to the target may be designed.
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37. Molecular Docking-
✓ It is a computational method to predict the
interaction of two molecule generation a binding
model.
✓ Docking is done between a small molecule and a
macromolecule.
✓ It is the study of how two or more molecular
structures fit together.
✓ It is an attempt to find best matching between two
molecules.
Types of docking-
✓ a) Rigid Docking
✓ b) Flexible Docking
✓ c) Manual Docking
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38. b) De novo Drug Design-
✓ It is the process in which 3D structure of
receptor is used to design newer
molecules.
✓ It involves structural determination of the
lead target complexes and lead
modifications using molecular modeling
tools.
✓ Information available about target receptor
but no existing leads that can interact.
Types of De novo Drug Design-
a) a) Atom based construction
b) b) Fragment based construction
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References
✓ Takenaka T (September 2001). "Classical vs reverse pharmacology in drug discovery". BJU Int. 88 Suppl 2: 7–10,
discussion 49–50. doi:10.1111/j.1464-410X.2001.00112.x. PMID 11589663. S2CID 30711746
✓ Gilson, M. K., Liu, T., Baitaluk, M., Nicola, G., Hwang, L., & Chong, J. (2016). BindingDB in 2015: A public
database for medicinal chemistry, computational chemistry and systems pharmacology. Nucleic Acids Research,
44(D1), D1045-D1053.
✓ Hopkins, A. L., & Groom, C. R. (2002). The druggable genome. Nature Reviews Drug Discovery, 1(9), 727-
730.Leach, A. R., Shoichet, B. K., &

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