3. Definition
Reverse pharmacology is the science of
integrating documented clinical/experiential hits,
into leads by transdisciplinary exploratory studies
and further developing these into drug candidates
by experimental and clinical research
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4. Scope
• Understand the mechanisms of action at multiple
levels of biological organization
• To optimize safety, efficacy and acceptability of
the leads in natural products, based on relevant
science
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5. Concept
• ‘Laboratory to clinic’ progress of discovery
pipeline to ‘Clinics to laboratories’.
• Conventional NCE Path :
• Reverse Pharmacology Path :
• ‘Safety’ remains the most important starting point
and the efficacy becomes a matter of validation
Molecule Mice Man
Man Mice Molecule
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7. DRUG DISCOVERY : CURRENT SCENARIO
• Incredible growth of pharmaceutical companies
due to the discovery of blockbuster drugs is
coming to an end.
• Average cost and time of discovering, developing
& launching a new drug is consistently increasing
without an expected corresponding increase in the
number of newer, safer and better drugs.
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8. • New molecular entities produced per company
have declined.
• The strategies that awarded success during the
past may not guarantee the same in the future.
• So the industry is facing a major challenge to
sustain and grow, which is resulting in many
merges, acquisitions or closures.
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9. Reverse pharmacology path
• Mass screening of plants for new leads/drugs –
expensive and inefficient.
• But traditional knowledge offered better leads
• 60% of anticancer & 75% of anti-infective drugs -
natural origins
• Cheaper and more productive to re-examine plant
remedies described in ancient texts
• Reduce bottlenecks of costs, time and toxicity
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10. • Active compounds from traditional medicine
serve as good scaffolds for rational drug design
part of routinely used traditional medicines
• Hence their tolerance and safety are relatively
better known than any other chemical entities that
are new for human use
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11. Traditional medicine
Modern medicine Modern science
Golden triangle – form a real discovery engine
that can result in newer, safer, cheaper and
effective therapies.
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12. Reverse Pharmacology in India
• Sir Ram Nath Chopra and Gananath Sen laid the
foundation of reverse pharmacology of ayurvedic
drugs
• Gananath Sen – pursuing clinically documented
effects of Ayurvedic drugs
• In 1931 - demonstrated the antihypertensive and
tranquilizing effect of Rawolfia serpentina
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13. • CSIR & ICMR - clinical trials with natural origin
• CCRAS – recently adopted the golden triangle
approach
• DRAVYAGUNA : ayurvedic study of drugs
derived from natural origin and becomes important
because of global acceptance of the ayurvedic
system of medicine
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14. • India has amended the Drug Act to include a
category of phyto-pharmaceuticals to be
developed from medicinal plants by Reverse
Pharmacology, with evidence of quality, safety
and efficacy
• These drugs will be distinct from traditional
medicines like Ayurvedic, Unani or Siddha
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16. Phases
1. EXPERIENTIAL :
It includes robust documentation of clinical
observations of the biodynamic effects of
standardized traditional drugs by meticulous
record keeping.
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17. 2. EXPLORATORY :
This phase includes the studies for tolerability,
drug interactions, dose range finding in ambulant
patients of defined subsets of the disease and para
clinical studies in relevant invitro & invivo
models to evaluate the target activity.
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18. 3. EXPERIMENTAL :
In basic & clinical, at several levels of
biological organization, to identify and validate
the reverse pharmacological correlates of drug
safety and efficacy
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19. Conventional vs Reverse pharmacology
21
Target
identificati
on &
validation
Lead
identificat
ion
Lead
optimizat
ion
Pre
clinical
studies
Clinical
trials
I,II,III
FDA
approval
& product
launch
TK
database
documented
clinical
use& safety
TK based
extract/
formulation
Fractionation
HTS
identification
of actives
Clinical
trials
Pre clinical
studies
Large
scale
clinical
trial
Pre clinical
study: validation
of efficacy
mechanism of
action
FDA
approval
& product
launch
Conventional : Time, Investment and Risk intensive
Discovery phase Development phase (10-15 yrs) 1-1.5 billion US$
RP : Faster, economical & safer
Discovery phase Development phase (5-6 yrs) 2-20 million US$
20. Reverse pharmacology – Examples
1. Zingiber officinale for Nausea/vomiting
2. Picrorhiza kuroa for Hepatitis
3. Curcuma longa for Oral cancer
4. Panchvalkal for Burns and wounds
5. Azadirachta indica for Malaria
6. Macuna pruriens for Parkinson’s disease
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22. Hurdles
• Despite a vast potential and possibilities - very
few success stories
• Most of the work in this field has remained within
clinics of traditional practitioners or confined to
academic research laboratories
• Improper experiential documentation
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23. • Lack of proper identity and implementation of
Good Laboratory Practices
• Absence of Phase II dose optimizing studies
• Cultural prejudice for alien science
• Lack of political and financial support
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25. Future Perspectives
• Many countries are increasingly aware of the
value of their traditional knowledge.
• Global pharmaceutical industry is looking for
innovative solutions to re-activate and reenergize
their discovery pipeline.
• Therefore, innovative approaches inspired by
traditional knowledge will remain important to
fast forward the discovery process
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26. Summary
• Traditional knowledge and experiential database
can provide new functional leads to reduce time,
money and toxicity
• These records are particularly valuable since those
medicines have been effectively tested for
thousands of years on people
• Normal drug discovery course of ‘Laboratory to
clinics’ becomes ‘Clinics to Laboratories’
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27. • India - offers immense opportunities for natural
product drug discovery and development based on
traditional knowledge and clinical observations
• Reverse pharmacology approaches need to be
further developed and optimized as novel means
for fast track drug discovery and development of
newer, safer & effective drugs
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28. References
• Rituparna maiti. Postgraduate topics in pharmacology
2nd edition. Hyderabad: PARAS; 2015.
• Patwardhan, B., 2008. Integrated Biomedical Research.
Proceedings, ICMR Symposium on Reverse
Pharmacology. Medical Research Centre of Kasturba
Health Society, Vile Parle
• (W), Mumbai, pp. 918. Vaidya, A.D.B., 2014. Reverse
Pharmacology A Paradigm Shift for Drug Discovery
and Development. Curr. Res. Drug Discov 1 (2), 3944.
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The traditional knowledge inspired reverse pharmacology relates to reversing the routine…
The credit for stimulating interest of Indian chemists and pharmacologists in medicinal plants should go to Sir Ram Nath Chopra who has been acclaimed as the ‘Father of Indian Pharmacology”
New Millennium Indian Technology Leadership Initiative (NMITLI) ; CCRAS -
CSIR – council for scientific and industrial research & ICMR have done clinical trials with natural products. Moreover central council for research in ayurveda and siddha …for some new indications of old drugs as well as for ayurveda
So reverse pharmacology is transdisciplinary aspect that is comprised of three phases or domains.
– the three main hurdles in the drug development
3. WITH TRADITIONAL MEDICINES NORMAL….
