It is a process of identification of new pharmacological indications from old/existing/failed/investigational/already marketed/FDA approved drugs/pro-drugs and the application of the newly developed drugs to the treatment of diseases other than the drug’s original/intended therapeutic use
2. CONTENTS
⮚Drug repurposing: Definition
⮚Introduction
⮚History
⮚Drug development process
⮚Traditional vs drug repurposing process
⮚Strategies of drug repurposing
⮚Approaches to drug repurposing
a. Computational
b. Experimental
c. Mixed
⮚Success stories
⮚Failure stories
⮚Challenges
⮚Applications
⮚Indian scenario
⮚Conclusion Dr. Prerana Manik Kadam 2
3. DRUG REPURPOSING
“ It is a process of identification of new pharmacological indications from
old/existing/failed/investigational/already marketed/FDA approved drugs/pro-
drugs and the application of the newly developed drugs to the treatment of
diseases other than the drug’s original/intended therapeutic use.”
Establish new therapeutic uses for :-
Already known
drugs
Failed Investigational Already marketed FDA approved Prodrug
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4. Drug repurposing
Drug re-tasking
Drug rescuing
Drug repositioning
Drug re-profiling
Drug recycling
Drug redirection Therapeutic switching
DRUG REPURPOSING
Renewing FAILED drugs + Expanding OLD drugs
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5. INTRODUCTION
Pharmaceutical industry-
generates 25% of the
annual revenue
Pharmaceutical industries 🡪
market growth - $ 6 billion
USD increase
One-third of the new
drug approvals are
repurposed drugs
30% of the
approved drugs and
biologics (vaccines)
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6. HISTORY
▪ Accidental discovery/serendipitous observations
▪ Marcell Johnson prescribed Sulfonamides during
the 2nd World War
▪ Adverse effect : Hypoglycemia, deaths due to
hypoglycemic coma
▪ Development of Antidiabetic agents from
Sulfonamides - Sulfonylureas
Best-known drug of this approach
Sildenafil
Original indication - Angina pectoris
New indication - Erectile dysfunction
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7. TRADITIONAL APPROACH
(Five stages)
Discovery and preclinical testing
Safety review
Clinical research
FDA review
FDA post-market safety monitoring
DRUG REPURPOSING
APPROACH
(Four stages)
Compound identification
Compound acquisition
Development
FDA post-market safety monitoring
DRUG DEVELOPMENT PROCESS
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9. TRADITIONAL
VS
DRUG REPURPOSING PROCESS
TRADITIONAL DRUG REPURPOSING
Unknown safety Known safety
Time-consuming
(10-17 years)
Less time than traditional
(6-10 years)
Costly
1.24 billion USD
Less expensive
<60%
High risk of failure
Drug present in market even
after failure
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11. DRUG - BASED
R1
R1 and R2 have similar profile
(structural characteristics, biological activities, adverse effects and
toxicities)
R1 can treat disease D, then R2 can also treat disease D
OLANZAPINE
ONDANSETRON
CINV
D
R2
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12. TARGET- BASED
• In silico screening or Virtual high-through-put screening
(vHTS) of drugs or compounds
Drug libraries
Compound databases
Selective protein molecule or a biomarker of interest
• Significant success rate - most biological targets directly
represent the disease pathways/mechanisms
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17. D1
Disease D1 and D2 have the same phenotype
A drug R that can treat disease D1, has the property to treat disease D2
D2
PULMONARY
HYPERTENSION
SILDENAFIL
R
DISEASE/THERAPY BASED
ERECTILE
DYSFUNCTION
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20. COMPUTATIONAL/ IN SILICO APPROACH
By using computational tools, virtually screening public
databases (drug/chemical) libraries
Uses computational biology and
bioinformatics/chemo- informatics tools
Identification of potential bioactive molecules - based upon the
molecular interaction between drug and target
Formulation of repurposing
hypotheses
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21. Publicly accessible
Target databases
• Drug bank
• Potential Drug
Target Database
• Therapeutic
Target Database
• Super Target
Ligand knowledge
bases
• World Drug Index
• MDI Drug data
report
• WOMBAT
• AurSCOPE
• ChemBioBase
• GVKBio
Online sources
• Prous
Investigational
drug database
• Adis Insight Trial
trove
• Information from
Patents,
conferences,
website etc.
Electronic
ORANGE BOOK
• US FDA
• DISC –
Discontinued drug
products
• Phase I –
withdrawn for
reasons other than
safety
DATA SOURCES
Information
about therapeutic targets
After
identifying therapeutic targets
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22. John Hopkins
clinical
compound
screening initiative
- 2002
- 3000 drugs
National Institute
of Health (NIH)
- 450 small
molecules
- History of use in
human clinical trials
NIH Chemical
Genomics Center
With NIH
Pharmaceutical
Collection (NPC)
- Drugs for human
trials
Novel public
private
partnership
initiative
- Access to Pfizer
indications
discovery unit
COMPOUND
LIBRARIES
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23. TYPES OF IN SILICO APPROACHES
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26. EXPRESSION PROFILE
• A strong negative correlation between
transcriptomic profile of drug and disease
will suggest potential effect of drug on
disease
Disease
Drug
• Analysis of transcriptomic profile between
drug and disease
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28. CHEMICAL STRUCTURE BASED
MOLECULAR
DOCKING
• Structure based computational
strategy
• To predict binding site
complimentary between ligand
and target
• Two types
Conventional
Inverse
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31. CLINICAL PROFILE - BASED
Two drugs cause
same adverse
effect
Suggests that
both may share
a target protein
or pathway
Adverse effect of
particular drug
may resemble a
disease
Suggests shared
pathways and
physiology by both
drug and disease
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35. NETWORK BASED
PATHWAY
Integrates multiple data
sources and combines
information regarding drugs
and their druggable targets to
predict potential drug
candidates
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40. DATA BASED – DATA MINING
Text mining is the discovery by computer of new, previously
unknown information by automatically extracting information from
different written sources
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43. EXPERIMENT BASED APPROACH
• Also known as Activity-based repositioning
• Protein target-based and cell/organism-based screens
in vitro and/or in vivo disease models
• No requirements of any structural information of
target proteins.
• Examples:
Target screening approach
Cell assay approach
Animal model approach
Clinical approach
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45. Cell based assay
Cancer cell
lines(CCLs)
Organism based
assay
Zebrafish
In vitro techniques
It can identify compounds
that show disease relevant
effects in animal model
systems without prior
knowledge target
PHENOTYPE
SCREENING
In vivo techniques
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47. OBSERVATIONS
IN PRE -
MARKETING
CLINICAL
STUDIES
Sildenafil
Phosphodiesterase 5 (PDE5) inhibitor
Compound developed as an
antihypertensive that produced
improved erectile function in clinical
trial patients
Finasteride
5 alpha-reductase inhibitor
repositioned from a benign prostatic
hyperplasia treatment to male pattern
baldness
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51. MIXED APPROACH
• Both in-silico and experimental approaches
• Result of computational methods is validated by pre-
clinical biological experiments (in vitro and in vivo
tests) and clinical studies.
• Balanced - robust and logical approach
ADVANTAGES
- Greater success than discovery based on serendipity
- Effective and rapid opportunities for repositioned drugs
- Reliable
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54. CHALLENGES
Many false positives
results from
computational methods
Data set integration
difficult as data is
• Complex
• Unstructured
New preclinical and/or
clinical trials may be needed
available data is unsatisfactory
and does not comply with the
requirements of regulatory
agencies
- IP protection is limited
- This prevents some
repositioned drugs from
entering even into the
market
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55. Using AI to integrate
Drug repositioning
Focus on Orphan
diseases
APPLICATIONS
Development of
Research sector of non
industrial entities
Diseases resistant to
treatment
Pandemic
situations
Precision
medicine
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56. WHO Special Program for Research and Training in
Tropical Diseases, Medicines for malaria venture, Drugs
for Neglected Diseases Initiative
Paromomycin and Miltefosine in Kala Azar
Open Source Drug Discovery (OSDD) – Drugs for
tropical infectious diseases
4000 genes for Mycobacterium tuberculosis and
proteins for which they code
Central Drug Research Institute- potent anti- HIV property of
Thiazolidinones
Previously Antibacterial
INDIAN SCENARIO
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57. CONCLUSION
Drug repurposing – advantageous. Therefore moving on
from serendipitous/accidental discovery approach to a New
‘Balanced’ approach is necessary.
Need for extensive research to create robust database with
respect to drug and disease profiles
Teach NEW tricks to an OLD drug
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