Reverse Pharmacology By Dr. Jeenal Mistry

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: 24
th
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
DrugTarget:
Cellular/molecularstructuresinvolvedinthepathophysiologyof
interestwheredrugindevelopmentismeanttoacton
Hit:
Acompoundwhichhasthedesiredactivity/robustdoseresponse
activityinacompoundscreenandknown,confirmedstructurewhose
activityisconfirmeduponretesting.

4. Key Words
4
Leads:
Arepresentativeofacompoundserieswithsufficientpotential
(measuredbypotency,selectivity,pharmacokinetic,physiochemical
properties,absenceoftoxicityandnovelty)toprogresstoafulldrug
developmentprogram.
Increasedactivityatachosentarget(Potency)
Reducedactivityagainstunrelatedtarget(Specificity)

5. Definition
5
ReversePharmacologyisdefinedas‘ascienceofintegrating
documentedexperimentalhits,intoleadsbytransdisciplinary
exploratorystudiesandfurtherdevelopingintodrugcandidatesby
experimentalresearch’.
Reverse Pharmacology RP+ =
Coming back to Pharmacology
Drug

6. History
6
SirRamNathChopra(FatherofIndian
Pharmacology)
Pioneerinthefieldofexperimental
pharmacologyofindigenousdrugsofIndia.
SirRamNathChopraandGananathSen
foundationofReversePharmacologyof
medicinalplantsbypursuingclinically
documentedeffectsofayurvedicdrugs.

7. History
7
GananathSenandKartikBosein1931demonstratedthe
antihypertensiveandtranquilizingeffectofRauwolfiaserpentina.
Alsoobserveduniquesideeffectssuchasdepression,extra
pyramidalsymptoms,gynecomastiaandpepticulcer.
Gananath Sen

8. Introduction
8
TheAyurvedicknowledgedatabase
Thenormaldrugdiscoverycourseof“Laboratoriestoclinics”
actuallybecomesfrom“Clinicstolaboratories”–aReverse
Pharmacologyapproach,withayurveda.

9. Introduction
9
Drugsweredevelopedfrommedicinalplants.
Example:Aspirin
Serendipity
Targetbaseddrugdiscoveryapproach

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
ManMiceMolecule

13. Scope
13
Discovernewdrugs
Mechanismofaction
Optimizeleads:safety,efficacyandacceptability
Newscientifictargetbaseddrugdiscoveryprocess

14. Need of Reverse
Pharmacology
14
Resistance
Urgenttofindnewhit&leadcompounds
Useofherbalmedicineisthefirstlinetreatmentinruralareas.

15. Stages of Reverse
Pharmacology
15
1.Experientialstage(Hit):
Identificationanddocumentation(recordkeeping)ofhits,
pharmacoepidemiologystudy.
Example:Bleedingwithaspirinuse

16. Stages of Reverse
Pharmacology
16
2.Exploratorystage(Lead):
Tolerability
Druginteraction
Doserangefinding
Preclinicalstudiesinvitroandinvivomodels

17. Stages of Reverse
Pharmacology
17
3.Experimentalstage(Target):
Basicscientificandclinicalresearchtodeterminesafety,efficacy
(preventiveortherapeutic)andmechanismofactionofthe
candidatedrug.
Example:aspirininducebleedingfollowedbyplateletsaggregation.

18. 18

19. Drug Discovery:
Current Scenario
19
Discoveryofblockbusterdrugs-Nolongerleadtohighgrowth
rates.
Theaveragecostandtimeofdiscovering,developingandlaunching
aNewdrug
NewMolecular/Chemicalentitiesproducedpercompanyhave
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
TheNumberofapprovalsfornewdrugshassteadilydeclined.
Researchanddevelopmentexpenseshaverisenfrom$2billionin
1980toover$83billionin2019.
10-15yearofinvestigationperiodandinvestmentofUS$1to1.5
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
Naturalproductdrugdiscovery,ethnopharmacology,traditional,
complementaryandalternativemedicinesarere-emergingasnew
strategicoptions
TheWHOcommission:affordablehealthsolutions
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
CharakSamhitaandSushrutSamhita
ReversePharmacologyusingnaturalproducts,'startwithhumans
andendswithhumans',whichensureitssafety.
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 (Blackpepper)
Psilocaulonabsimile
Petrosimoniamonandra
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-thalidomidein multiple myeloma
Botulinumin dystonia and blepharospasm
Hydroxyureafor the induction of fetal haemoglobin
Aspirinfor platelet aggregation inhibition
Vitamin K2-7 for muscle cramps

43. 43
Reverse
Pharmacology
in India

44. Reverse Pharmacology in
India
44
Recently,IndianCouncilofMedicalResearch(ICMR)has
establishedanadvancedcenterofreversepharmacologyatSwami
PrakashanandaAyurvedaResearchCentre,Mumbai,wherethe
researchfocusison
Diabetes
Musculo-skeletalhealth
Malaria
Cancer
Neuronalplasticity

45. Reverse Pharmacology
in India
45
CouncilforScientificandIndustrialResearch(CSIR)throughthe
NewMillenniumIndianTechnologyLeadershipInitiative
(NMITLI)
TheNMITLI:multi-institutional,multi-disciplinaryendeavorin
Diabetes,Psoriasis,Osteoarthritis,Hepatitis.

46. Guggulipid
46
CompositedrugresearchprogramjointlyconductedbyIndian
CouncilofMedicalResearchandCouncilforScientificand
IndustrialResearchofGovernmentofIndia
GuggulipidwasdevelopedfromCommiphoraMukul
takingtheleadfromAyurveda
DrugControllerGeneralofIndia(DCGI)approvedthedrugfor
marketingin1986
GuggulipidisbeingmanufacturedandmarketedbyCipla,Guglip

47. Nyctanthes
arbortristis Linn
47
NightfloweringJasmine
Antimalarialactivity
Completeparasiteeradicationandclinicalcurewithin7daysof
treatmentwithleafpasteofNyctanthesarbortristisLinn
Plantextractsshownantiplasmodiumeffectsinvitroanddisease
modifyingactivityinpatients

48. Nyctanthes
arbortristis Linn
48
IndianCouncilofMedicalResearch-Advancedcenterofreverse
pharmacologyintraditionalmedicine,incollaborationwiththe
CenterofMolecularParasitologyattheDrexelUniversityCollege
ofMedicine,Philadelphiaforfurtherevaluationoftheproduct.

49. Case Studies
49

50. Artemisinin
50
Herbartemisiaannuahasbeenusedformanycenturiesin
TraditionalChineseMedicineastreatmentforfeverandmalaria
In1971,Artemisininfromtheleafyportionsoftheplant
Artemisininanditsderivativesofferpromiseasanewclassof
antimalarials
Bestcaseforreversepharmacologyapproach
Anti-cancer,asthmaandantioxidantproperties

51. Psoriasis
51
UnderNewMillenniumIndianTechnologyLeadershipInitiative
project,LupinLaboratories(India)attempteddevelopmentofa
singleplantbasedoralherbalformulationthroughReverse
Pharmacology
Thedrugcandidate(Desoris)isanherbalbeneficiatedextractof
leavesofArgemoneMexicana
Novelmechanismofactionandeffectivelymodulatesthecellular
functionleadingtopsoriaticlesionimprovement

52. Psoriasis
52
Extensivestudiescomprising:Toxicology
Efficacy
Safety
Pharmacokinetics
Pharmacodynamics
LupincompletedthePhaseIclinicaltrialinSeptember2004and
PhaseIIclinicaltrialin2005
ThisdrughasbeendevelopedconformingtotheUSFDAguidelines
forbotanicalsandDCGInormsonnewdrugdevelopment

53. Psoriasis
53
Expectations-5-6yearsandcostUS$5millionasagainstroutine10-
15yearsandUS$1-1.5billion
CostUS$50,quiteastepdownfromanewUS$20,000antibody
injection

54. Parkinson's disease
54
MucunapruriensseedsforthetreatmentofParkinson’sDisease
3.1-6.1%L-DOPAwithtraceamountsofserotonin&nicotine
Anti-venom,LibidoandFertility,Neuroprotection

55. Parkinson's disease
55
CollaborationbetweenAcademiaandZanduPharmaceuticalWorks
(Mumbai)
TheirteamconductedseriesofexperimentsonMucunatodevelopa
naturaldrugforParkinson'sdisease

56. Parkinson's disease
56
TheUSFDAapprovedNewDrugApplicationforclinicalstudies
L-dopavsMucuna
MucunaPrurienswasnotedlessdyskinesia
HypothesizedtohaveunknownDopamineDecarboxylaseinhibitor
ZandopaisnowapprovedbytheIndianregulatoryZANDU
Thisstandardized,safeandeconomicalnaturalproductZandopacan
effectivelyreplacesyntheticL-DOPAformulation

57. Osteoarthritis
57
Thepreclinicalevaluationwasdesigned&theassayinvolvedtargets
relevanttoinflammation,pain,immunomodulationand
chondroprotectioninamodelofosteoarthriticcartilagedamage
ShortlistedformulationsenteredseriesofRandomizedControlTrial
withglucosamineandcelecoxib
Thisprojectwascompletedin5yearswithexpenditureofoverUS$
2million

58. Osteoarthritis
58
CostjustUS$25:chondroprotection
CouncilforScientificandIndustrialResearchidentifying
development,optimization,manufacturing,registrationsand
marketing
Theprojectusedtraditionalknowledgeguidedplatform:Toobtain
desiredtherapeuticactivities
GoodManufacturingPractices

59. Vaccine Adjuvant
59
InterdisciplinarySchoolofHealthSciences,UniversityofPune
withSerumInstituteofIndiaasanindustrypartner,tookupa
projectsupportedbyDepartmentofScience&Technology(DST),
Govt.ofIndia,todevelopherbalvaccineadjuvant,i.e.Alumsalts.
Semi-pureleads:Efficacyagainstpolysaccharide,toxoidand
recombinantgroupofvaccines.

60. Recent Studies
60
TherapeuticplantsofSiddhaMedicinehavingAnticancereffects:A
Review
In-vitroproteindenaturationinhibitionassayofSivapputhailaman
anti-inflammatorySiddhatherapeuticoil.
ACasereportontheSiddhaManagementofNonHealing
NecrotizingDiabeticfootulcer.
International Journal of Reverse Pharmacology and Health Research (IJRPHR)

61. 61
Herbs Use
Alangium salviifoliumEhrlich 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 roseusLeukemia and lymphoma
Garcinia indica Colon cancer
Ethel Shiny S 1 , SobanaVallee 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 , SobanaVallee 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 amarusDalton’s lymphoma ascites (DLA) and Ehrlich
ascites carcinoma (EAC)
Andrographis paniculataJaundice, 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 , SobanaVallee 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 /GingerGastriccancer,cancersofovary,cervix,
colon,rectum,liver,urinarybladder,oral
cavity,neuroblastomaandleukaemia
Nigella sativa Cancersofthecolon,prostate,pancreas,
uterus,malignantascites,malignant
lymphoma, malignantmelanoma,
sarcomasandleukaemia
Plumbago zeylanica Breast cancer, liver cancer, fibrosarcoma,
malignant ascites and leukaemia
Psoralea corylifoliaLung 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. ntJ Rev Pharmacology Health Res Volume 4, Issue 4, Oct-Dec, 2021
Herbs Use
Pongamia pinnata PierreSkindiseasesInflammationsDiabetic
Rubia cordifolia LinnSkindiseasesWoundInflammationDiabetic
Hemidesmus indicusSkin diseases Inflammation Syphilis Urinary
disorders
Manjal mezhugu Skin diseases Wound Inflammations
Vateria indica LinnSkin 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 ulcerMaththan thylam
Triphala powder

66. Hurdles
66
Veryfewsuccessstories.
Improperexperientialdocumentation
Lackofproperidentityandimplementation
Lackoffunctionallywellstructuredmultisystemand
multidisciplinaryorganization
Absenceoftechnicalandscientificcontributions:significantly
delayeddrugdiscoveries

67. Future Perspectives
67
Awareness
ReactivateandRe-energizediscoverypipeline
NMITLI:Hits,leadsandeffectiveformulationsfordiabetes,
arthritisandhepatitiswithnovelmechanismofactionandintellectual
property
Phytopharmaceuticals:Evidenceofquality,safetyandefficacy

68. Conclusion
68
Newfunctionalleadtoreducetime,moneyandtoxicity
Needofthetime-todocumentunknown,unintendedanddesirable
novelprophylacticandtherapeuticeffectsinobservational
therapeutics
Fasttrackdrugdiscoveryanddevelopmentofnewer,saferand
effectivedrugs.

69. References
69
ParasMedicalPublicationofPostgraduatePharmacologyfrom
SougataSarkar,VartikaSrivastava,ManjushreeMohanty
PostGraduatetopicsinPharmacology3
rd
editionfromRituparnamaiti
InternationalJournalofReversePharmacologyandHealthResearch
(IJRPHR)
R.C.MohsandN.H.Greig/Drugdiscoveryanddevelopment:Roleof
basicbiologicalresearch/Alzheimer’s&Dementia:Translational
Research&ClinicalInterventions3(2017)651-657

70. 70