The goal of reverse pharmacology is to utilize disease pathology in order to identify specific and targetable elements that novel compounds can be modeled from.

1. Reverse
Pharmacology
Dr. Jeenal Mistry
Second year resident,
Dept. of Pharmacology,
Government Medical College, Surat.
Date: 24th February 2022

2. Outlines
2
Definition
History
Introduction
Scope
Need of Reverse Pharmacology
Stages
Reverse Pharmacology in Drug
Discovery: Current Scenario
Ayurveda with Reverse
Pharmacology
Examples of Reverse Pharmacology
Reverse Pharmacology in India
Recent studies
Hurdles
Future Perspectives
Conclusion

3. Key Words
3
Drug Target:
Cellular/molecular structures involved in the pathophysiology of
interest where drug in development is meant to act on
Hit:
A compound which has the desired activity/robust dose response
activity in a compound screen and known, confirmed structure whose
activity is confirmed upon retesting.

4. Key Words
4
Leads:
A representative of a compound series with sufficient potential
(measured by potency, selectivity, pharmacokinetic, physiochemical
properties, absence of toxicity and novelty) to progress to a full drug
development program.
Increased activity at a chosen target (Potency)
Reduced activity against unrelated target (Specificity)

5. Definition
5
Reverse Pharmacology is defined as ‘a science of integrating
documented experimental hits, into leads by transdisciplinary
exploratory studies and further developing into drug candidates by
experimental research’.
Reverse Pharmacology RP
+ =
Coming back to Pharmacology
Drug

6. History
6
Sir Ram Nath Chopra (Father of Indian
Pharmacology)
Pioneer in the field of experimental
pharmacology of indigenous drugs of India.
Sir Ram Nath Chopra and Gananath Sen
foundation of Reverse Pharmacology of
medicinal plants by pursuing clinically
documented effects of ayurvedic drugs.

7. History
7
Gananath Sen and Kartik Bose in 1931 demonstrated the
antihypertensive and tranquilizing effect of Rauwolfia serpentina.
Also observed unique side effects such as depression, extra
pyramidal symptoms, gynecomastia and peptic ulcer.
Gananath Sen

8. Introduction
8
The Ayurvedic knowledge database
The normal drug discovery course of “Laboratories to clinics”
actually becomes from “Clinics to laboratories” – a Reverse
Pharmacology approach, with ayurveda.

9. Introduction
9
Drugs were developed from medicinal plants.
Example: Aspirin
Serendipity
Target based drug discovery approach

10. Reverse Pharmacology:
Trans-Discipline
10
Reverse
Pharmacology
Modern
Science
& Technology
Traditional
Medicine
Modern
Medicine

11. 11

12. Concept of Reverse
Pharmacology
12
Reverse Pharmacology
Conventional approach
Safety
Man
Mice
Molecule

13. Scope
13
Discover new drugs
Mechanism of action
Optimize leads: safety, efficacy and acceptability
New scientific target based drug discovery process

14. Need of Reverse
Pharmacology
14
Resistance
Urgent to find new hit & lead compounds
Use of herbal medicine is the first line treatment in rural areas.

15. Stages of Reverse
Pharmacology
15
1. Experiential stage (Hit):
Identification and documentation (record keeping) of hits,
pharmacoepidemiology study.
Example: Bleeding with aspirin use

16. Stages of Reverse
Pharmacology
16
2. Exploratory stage (Lead):
Tolerability
Drug interaction
Dose range finding
Pre clinical studies in vitro and in vivo models

17. Stages of Reverse
Pharmacology
17
3. Experimental stage (Target):
Basic scientific and clinical research to determine safety, efficacy
(preventive or therapeutic) and mechanism of action of the
candidate drug.
Example: aspirin induce bleeding followed by platelets aggregation.

18. 18

19. Drug Discovery:
Current Scenario
19
Discovery of blockbuster drugs- No longer lead to high growth
rates.
The average cost and time of discovering, developing and launching
a New drug
New Molecular/ Chemical entities produced per company have
declined
R.C. Mohs and N.H. Greig / Drug discovery and development: Role of basic biological research/ Alzheimer’s & Dementia: Translational Research &
Clinical Interventions 3(2017) 651-657

20. Drug Discovery:
Current Scenario
20
The Number of approvals for new drugs has steadily declined.
Research and development expenses have risen from $ 2 billion in
1980 to over $ 83 billion in 2019.
10-15 year of investigation period and investment of US $ 1 to 1.5
billion
R.C. Mohs and N.H. Greig / Drug discovery and development: Role of basic biological research/ Alzheimer’s & Dementia: Translational Research &
Clinical Interventions 3(2017) 651-657

21. Drug Discovery:
Current Scenario
21
Natural product drug discovery, ethnopharmacology, traditional,
complementary and alternative medicines are re-emerging as new
strategic options
The WHO commission : affordable health solutions
R.C. Mohs and N.H. Greig / Drug discovery and development: Role of basic biological research/ Alzheimer’s & Dementia: Translational Research &
Clinical Interventions 3(2017) 651-657

22. Ayurveda in Reverse
Pharmacology
22
Charak Samhita and Sushrut Samhita
Reverse Pharmacology using natural products, 'start with humans
and ends with humans', which ensure its safety.
Functional
activity
Desired
physiological
effect
Receptors
(targets)

23. Ayurveda in Reverse
Pharmacology
23
Ayurveda
vis-à-vis
Reverse
Pharmacology
The Discovery Engine
Science
(Experiments)
Ayurveda
(drayavaguna)
Modern
Medicine
(Clinical
branch)

24. Examples of Reverse
Pharmacology Success
24
Promising lead molecules that have come out of
Reverse Pharmacology
1. Rauwolfia Serpentina (Sarpagandha)
Alkaloids
Use: Anti-hypertensive
Incidental Discovery: Anti-depressant

25. Examples of Reverse
Pharmacology Success
25
2. Psoralea corylifolia (Babchi)
Use: Anti-vitiligo
Incidental Discovery: PUVA –therapy,
Alopecia

26. Examples of Reverse
Pharmacology Success
26
3. Berberis aristata (Indian barberry)
Use: Anti-infective
Incidental Discovery: Septic shock,
Anti-malarial

27. Examples of Reverse
Pharmacology Success
27
4. Picrorhiza kurroa (Kutki)
Use: Hepatic protection
Incidental Discovery: Hydrocholeretic,
Anti- asthma

28. Examples of Reverse
Pharmacology Success
28
5. Commiphora wightii (Gugal)
Use: Hypolipidemic agents
Incidental Discovery: Anti-arthritic,
Anti-obesity

29. Examples of Reverse
Pharmacology Success
29
6. Curcuma longa (Turmeric/Haldi)
Use: Anti-inflammatory
Incidental Discovery: Cancer-preventive

30. Examples of Reverse
Pharmacology Success
30
7. Azadirachta indica (Neem)
Use: Antifungal, Antibacterial,
Antiviral
Various skin diseases like eczema,
Psoriasis
Incidental Discovery: Anti cancer,
Anti-malarial

31. Examples of Reverse
Pharmacology Success
31
8. Phyllanthus emblica (Amla)
Use: Anti-aging, Anti-inflammatory
Anti-oxidant Anti-microbial
CNS stimulant Hypoglycaemic
Anti-cancerous Hair growth promoter
Anti reproductive effect Digestive system disorder

32. Examples of Reverse
Pharmacology Success
32
9. Tinospora cordifolia (Guduchi)
Use: Skin Infection, Respiratory Infection
Specially in diabetic and immunocompromised person

33. Examples of Reverse
Pharmacology Success
33
10. Carica papaya (Papita)
Use: For Platelets production
Antifertility
Anti-implantation

34. Examples of Reverse
Pharmacology Success
34
11. Wrightia antidysenterica (Holarrhena)
Alkaloids
Use: Amoebiasis
Diarrhoea
Inflammatory bowel disease
Haemorrhoids
Liver disorders

35. Examples of Reverse
Pharmacology Success
35
12. Mucuna pruriens (Bengal velvet bean)
Use: Parkinson's disease, Snake bite

36. Examples of Reverse
Pharmacology Success
36
13. Piperidines (Black pepper)
Psilocaulon absimile
Petrosimonia monandra
Use: As bioavailability enhancer

37. Examples of Reverse
Pharmacology Success
37
14. Baccosides (Brahmi)
Bacopa monnieri
Use: Memory Enhancer

38. Examples of Reverse
Pharmacology Success
38
15. Withania somnifera (Ashwagandha)
Use: Immunomodulators Memory enhancing
Anti-inflammatory Antivenom
Anti-stress Antidiuretic
Antioxidant

39. Examples of Reverse
Pharmacology Success
39
16. Zingiber officinale (Ginger)
Use: Nausea/ Vomiting

40. Examples of Reverse
Pharmacology Success
40
17. Forskolin
Alkaloid
Isolated from coleus froskohlii & Stephania glabra
Use: anti-obesity, Atherosclerosis

41. Identification of new
indication of an old drug
(Drug repurposing) by
Reverse Pharmacology
41

42. 42
L-thalidomide in multiple myeloma
Botulinum in dystonia and blepharospasm
Hydroxyurea for the induction of fetal haemoglobin
Aspirin for platelet aggregation inhibition
Vitamin K2-7 for muscle cramps

43. 43
Reverse
Pharmacology
in India

44. Reverse Pharmacology in
India
44
Recently, Indian Council of Medical Research (ICMR) has
established an advanced center of reverse pharmacology at Swami
Prakashananda Ayurveda Research Centre, Mumbai, where the
research focus is on
Diabetes
Musculo-skeletal health
Malaria
Cancer
Neuronal plasticity

45. Reverse Pharmacology
in India
45
Council for Scientific and Industrial Research (CSIR) through the
New Millennium Indian Technology Leadership Initiative
(NMITLI)
The NMITLI : multi-institutional, multi-disciplinary endeavor in
Diabetes, Psoriasis, Osteoarthritis, Hepatitis.

46. Guggulipid
46
Composite drug research program jointly conducted by Indian
Council of Medical Research and Council for Scientific and
Industrial Research of Government of India
Guggulipid was developed from Commiphora Mukul
taking the lead from Ayurveda
Drug Controller General of India (DCGI) approved the drug for
marketing in 1986
Guggulipid is being manufactured and marketed by Cipla, Guglip

47. Nyctanthes
arbortristis Linn
47
Night flowering Jasmine
Anti malarial activity
Complete parasite eradication and clinical cure within 7 days of
treatment with leaf paste of Nyctanthes arbortristis Linn
Plant extracts shown anti plasmodium effects in vitro and disease
modifying activity in patients

48. Nyctanthes
arbortristis Linn
48
Indian Council of Medical Research - Advanced center of reverse
pharmacology in traditional medicine, in collaboration with the
Center of Molecular Parasitology at the Drexel University College
of Medicine, Philadelphia for further evaluation of the product.

49. Case Studies
49

50. Artemisinin
50
Herb artemisia annua has been used for many centuries in
Traditional Chinese Medicine as treatment for fever and malaria
In 1971, Artemisinin from the leafy portions of the plant
Artemisinin and its derivatives offer promise as a new class of
antimalarials
Best case for reverse pharmacology approach
Anti-cancer, asthma and anti oxidant properties

51. Psoriasis
51
Under New Millennium Indian Technology Leadership Initiative
project, Lupin Laboratories (India) attempted development of a
single plant based oral herbal formulation through Reverse
Pharmacology
The drug candidate (Desoris) is an herbal beneficiated extract of
leaves of Argemone Mexicana
Novel mechanism of action and effectively modulates the cellular
function leading to psoriatic lesion improvement

52. Psoriasis
52
Extensive studies comprising : Toxicology
Efficacy
Safety
Pharmacokinetics
Pharmacodynamics
Lupin completed the Phase I clinical trial in September 2004 and
Phase II clinical trial in 2005
This drug has been developed conforming to the US FDA guidelines
for botanicals and DCGI norms on new drug development

53. Psoriasis
53
Expectations-5-6 years and cost US $5 million as against routine 10-
15 years and US $ 1-1.5 billion
Cost US $ 50, quite a step down from a new US $ 20,000 antibody
injection

54. Parkinson's disease
54
Mucuna pruriens seeds for the treatment of Parkinson’s Disease
3.1-6.1% L-DOPA with trace amounts of serotonin & nicotine
Anti-venom, Libido and Fertility, Neuroprotection

55. Parkinson's disease
55
Collaboration between Academia and Zandu Pharmaceutical Works
(Mumbai)
Their team conducted series of experiments on Mucuna to develop a
natural drug for Parkinson's disease

56. Parkinson's disease
56
The US FDA approved New Drug Application for clinical studies
L-dopa vs Mucuna
Mucuna Pruriens was noted less dyskinesia
Hypothesized to have unknown Dopamine Decarboxylase inhibitor
Zandopa is now approved by the Indian regulatory ZANDU
This standardized, safe and economical natural product Zandopa can
effectively replace synthetic L-DOPA formulation

57. Osteoarthritis
57
The preclinical evaluation was designed & the assay involved targets
relevant to inflammation, pain, immunomodulation and
chondroprotection in a model of osteoarthritic cartilage damage
Short listed formulations entered series of Randomized Control Trial
with glucosamine and celecoxib
This project was completed in 5 years with expenditure of over US $
2 million

58. Osteoarthritis
58
Cost just US $ 25: chondroprotection
Council for Scientific and Industrial Research identifying
development, optimization, manufacturing, registrations and
marketing
The project used traditional knowledge guided platform : To obtain
desired therapeutic activities
Good Manufacturing Practices

59. Vaccine Adjuvant
59
Interdisciplinary School of Health Sciences, University of Pune
with Serum Institute of India as an industry partner, took up a
project supported by Department of Science & Technology (DST),
Govt. of India, to develop herbal vaccine adjuvant, i.e. Alum salts.
Semi-pure leads : Efficacy against polysaccharide, toxoid and
recombinant group of vaccines.

60. Recent Studies
60
Therapeutic plants of Siddha Medicine having Anticancer effects : A
Review
In-vitro protein denaturation inhibition assay of Sivappu thailam an
anti-inflammatory Siddha therapeutic oil.
A Case report on the Siddha Management of Non Healing
Necrotizing Diabetic foot ulcer.
International Journal of Reverse Pharmacology and Health Research (IJRPHR)

61. 61
Herbs Use
Alangium salviifolium Ehrlich Ascites Carcinoma (EAC)
Centella asiatica Human breast cancer
Crocus sativus Human tongue squamous cell Carcinoma
Boerhavia diffusa Dimethyl benza anthracene induced cancer
Vitis vinifera Ehrlich ascites carcinoma (EAC)
Catharanthus roseus Leukemia and lymphoma
Garcinia indica Colon cancer
Ethel Shiny S 1 , Sobana Vallee Narayan S. R Therapeutic plants of Siddha Medicine having Anticancer effects : A Review Int J Rev
Pharmacology Health Res Volume 2, Issue 2, Apr-Jun 2019

62. 62
Ethel Shiny S 1 , Sobana Vallee Narayan S. R Therapeutic plants of Siddha Medicine having Anticancer effects : A Review Int J Rev
Pharmacology Health Res Volume 2, Issue 2, Apr-Jun 2019
Herbs Use
Phyllanthus amarus Dalton’s lymphoma ascites (DLA) and Ehrlich
ascites carcinoma (EAC)
Andrographis paniculata Jaundice, cholestasis
Catharanthus roseus Cancer, diabetes, fever and hypertension
Ficus carica Colon cancer, leukemia
Curcuma longa Breast cancers, prostate cancer
Azadirachta indica Cancers of breast, lung, stomach, prostate and
skin

63. 63
Ethel Shiny S 1 , Sobana Vallee Narayan S. R Therapeutic plants of Siddha Medicine having Anticancer effects : A Review Int J Rev
Pharmacology Health Res Volume 2, Issue 2, Apr-Jun 2019
Herbs Use
Zingiber officinale /Ginger Gastric cancer, cancers of ovary, cervix,
colon, rectum, liver, urinary bladder, oral
cavity, neuroblastoma and leukaemia
Nigella sativa Cancers of the colon, prostate, pancreas,
uterus, malignant ascites, malignant
lymphoma, malignant melanoma,
sarcomas and leukaemia
Plumbago zeylanica Breast cancer, liver cancer, fibrosarcoma,
malignant ascites and leukaemia
Psoralea corylifolia Lung cancer, liver cancer, osteosarcoma,
fibrosarcoma, malignant ascites and
leukaemia

64. 64
Archana K1 , Mahadevan MVIn-vitro protein denaturation inhibition assay of Sivappu thailam an anti-inflammatory Siddha therapeutic
oil. nt J Rev Pharmacology Health Res Volume 4, Issue 4, Oct-Dec, 2021
Herbs Use
Pongamia pinnata Pierre Skin diseases Inflammations Diabetic
Rubia cordifolia Linn Skin diseases Wound Inflammation Diabetic
Hemidesmus indicus Skin diseases Inflammation Syphilis Urinary
disorders
Manjal mezhugu Skin diseases Wound Inflammations
Vateria indica Linn Skin diseases Nervous disorder Arthritis
Dioscorea purpurea /
Dioscorea alata
Skin diseases

65. Recent Studies
65
Sangeetha M.K1 , Rajkumar KA Case report on the Siddha Management of Non Healing Necrotizing Diabetic foot ulcer. Int J Rev
Pharmacology Health Res Volume 4, Issue 1, Jan-Mar, 2021
Herbs Use
Aavarai kudineer chooranam
Non Healing Necrotizing Diabetic foot ulcer
Maththan thylam
Triphala powder

66. Hurdles
66
Very few success stories.
Improper experiential documentation
Lack of proper identity and implementation
Lack of functionally well structured multisystem and
multidisciplinary organization
Absence of technical and scientific contributions : significantly
delayed drug discoveries

67. Future Perspectives
67
Awareness
Reactivate and Re-energize discovery pipeline
NMITLI : Hits, leads and effective formulations for diabetes,
arthritis and hepatitis with novel mechanism of action and intellectual
property
Phytopharmaceuticals : Evidence of quality, safety and efficacy

68. Conclusion
68
New functional lead to reduce time, money and toxicity
Need of the time- to document unknown, unintended and desirable
novel prophylactic and therapeutic effects in observational
therapeutics
Fast track drug discovery and development of newer, safer and
effective drugs.

69. References
69
Paras Medical Publication of Postgraduate Pharmacology from
Sougata Sarkar, Vartika Srivastava, Manjushree Mohanty
Post Graduate topics in Pharmacology 3rd edition from Rituparna maiti
International Journal of Reverse Pharmacology and Health Research
(IJRPHR)
R.C. Mohs and N.H. Greig / Drug discovery and development: Role of
basic biological research/ Alzheimer’s & Dementia: Translational
Research & Clinical Interventions 3(2017) 651-657

70. 70