New Drug Discovery From Medicinal Plants/ Natural Products

Dabur Research Foundation, Sahibabad

Ancient Egyptian, Chinese, and Indian Literature

Plant-based remedies and preventives as a major part of treatments

Out of a total of 520 new drugs approved in last two decades: 30 were new Natural Products and 127 were chemically modified Natural Products

Natural Products as a part of Traditional Medicinal System

Prominent Plant Based Drugs of Last century

Quinine, anti-malarial drug, from the bark of Cinchona sp.

Morphine, analgesic, from the opium poppy

Digoxin, for heart disorders, from Digitalis purpurea

Reserpine, Antihypertensive agent, from Rauwolfia serpentina

Ephedrine, anti-asthma agent, from Ephredra sinica

Tubocurarine, muscle relaxant, from Chondrodendron and

Curarea species

Natural Products as Source of Lead Compounds

Bio-diversity

Novel Molecular structures

Advances in Chemistry and Biology

Radical opportunities in New Drug Discovery

Molecular components of Disease Process as Drug Targets

High Throughput Chemistry & High Throughput Screening

Increasing speed of Drug Discovery Process ?

“whether the previously most successful source of drugs (i.e. Natural Products) has any place in modern drug discovery?”

Approaches for New Drug Discovery

The Traditional Approach

Trial and error based on reports from different cultures and systems of medicine.

e.g.Morphine, Quinine and Ephedrine

The Empirical Approach Understandings of a relevant physiological process. Often

develops a therapeutic agent from a naturally occuring lead molecule. e.g.Tubocurarine and other muscle relaxants, Propranolol and other β-adrenoceptors antagonists,

The Molecular ApproachAvailability or understanding of a molecular target for the medicinal agent.Majority of drug discovery is currently based on the

Molecular Approach.

The Molecular Approach Of Drug Discovery

Rational Drug Design:

Based on Computer Aided Techniques

Antisense Approach:

Manipulation of Genetic Targets

Pragmatic Approach:

Random Screening of chemical diversity

Sources of compounds Therapeutic Targets

Chemical Libraries

Historical Compound Collection

Natural Product Libraries

Combinatorial Libraries

Traditional medicinal uses of Natural Products

Impirical understanding of Physiology

Molecular cloning of receptors and signalling molecules

Rational Synthesis

Antisense Oligonucleotides

Drug Discovery Screening Assays

Lead Optimization Drug Development

Sources and Approaches for Drug Discovery

Redesigning Drug Discovery:

Natural Products in High Throughput Era

Conventional Bioassays

10,000 /yr

High Throughput Screening

100,000 /day

Combinatorial Chemistry

• Peptides and Oligonucleotide libraries

• Small drug-like molecules

Natural Product Libraries

• Greater chemical/ Structural Diversity

• Natural Products are relatively smaller

(>1000Da)

New Chemical Entities Organized by Source/Year

6

98

3

8

2

10

4

8 8

3

20

2

1

6

2

2

2

3

1

5

8

2

1

9

810

013

14

12

8

7

0

0

12

12

0

0

189

14

1413

12 12

12

8

9

12

5

5

38

2

4

6

58

15

10

6

3

2

6

75

2

4

3

5 8 8 5 4

7

3

4

10

13

12 2 1

2 2

7

1 1

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

Year

Num

ber

of N

CE

s

V

S*

NM

S

ND

N

B

B: Biological; N: Natural Product, ND: Derived from NP, semisynthetic; S*: Total synthetic; S = semisynthetic NM: Natural Product Mimic; V: vaccine

Source: J.Nat.Pr.; 66(7); 2003.

NCEs by source, 1981-2002

B12%

N5%

ND23%

S33%

NM20%

S*4%

V3%

B

N

ND

S

NM

S*

V

•Around 52% of the Novel molecules are either Natural Products or Natural Product derivatives

•60 - 80% of Anti-Bacterial, and Anti- Cancer drugs are derived from Natural Products

-Cragg et al.; J. Nat.Pr. 60(3)

Many pharmaceutical companies deemphasized natural product research in favor of high- throughput screening of mass-produced combinatorial libraries

The expectation was rich rewards in terms of multiplicity of novel drugs and resultant revenue windfalls

Early 90s

Beyond Yr. 2000

The number of NCEs hit the 20 year low ( Only 37 in 2001)

FDA received only 16 NDAs in 2001, as compared to 24 in 2000

Need to emphasize on Natural Products research in the search for new therapeutic molecules

Natural Products as Sources of New drugs: A Review

•Natural Product Sources: Plants, Microorganisms, Animals, Marine organisms

•Molecules with the broadest range of therapeutic application have mostly been obtained from the plant kingdom

Microorganisms: “The Golden Age of ANTIBIOTICS”

Anti-bacterial agents from Penicillium species Immunosuppressants: Cyclosporins & Rapamycin, from Streptomyces sp. Cholesterol lowering agents: Mevastatin & Lovastatin, from Penicillium sp. Anthelmintics and antiparasitic drugs, such as the ivermectins, from

Streptomyces

Oceans and Marine organisms as a vast resource for new therapeutic agents

Pseudopterosins, with significant analgesic and anti-inflammatory properties,

from the Caribbean gorgonian Pseudopterogorgia elisabethae

Manoalide, an anti-inflammatory agent, from the sponge Luffarriella variabilis

Ziconotide and other new painkillers derived from peptides from cone snail

venom

Natural Products as Sources of New drugs…...

Several key anti-cancer agents have been produced from natural sources

Vinblastine & vincristine from Madagascar periwinkle, Catharanthus

rosesus

Etoposide and teniposide : Semi-synthetic derivatives of Epipodophyllotoxin

Taxol: From the bark of Taxus brevifolia in the northwestern United States

Natural Products: Lead for semisynthetic/synthetic modification

•Diosgenin (Dioscorea sp.) Anabolic steroids, Anti- inflammatory, Oral Contraceptives

•Morphine

(Papaver somniferum)

Levophenol, Pentazocine

•Ephedrine & Pseudoephedrine: Prepared commercially by total synthesis

•Analogs of a lead molecule may exhibit unexpected biological activity, and then can be modified synthetically even further.e.g. Mepiridine (pethidine) was found to have analgesic activity, which was discovered during screening of a series of compounds intended as anticholinergic agents based on the plant derived alkaloid, atropine. Structural modification of meperidine led to haloperidol series of neuroleptics.

Anti-cancer alkaloid Vinorelbine: Semisynthetic Natural Analog with high therapeutic activity.

Derived from alkaloids of Vinca rosea in mid 90s.

Highly potent in Breast cancers, Testicular cancers, Epithelial ovarian cancers, and Non-small cell lung cancers.

Natural Product Drug Therapeutic Action SourceAcetyldigoxin Cardiotonic Digitalis lanata (Grecian

foxglove, woolly foxglove)Aesculetin Antidysentery Frazinus rhychophyllaArecoline Anthelmintic Areca catechu (betel nut palm)

Asiaticoside Vulnerary Centella asiatica (gotu cola)Betulinic acid Anticancerous Betula alba (common birch)

Caffeine CNS stimulant Camellia sinensis (tea, alsocoffee, cocoa and other plants)

Camptothecin Anticancerous Camptotheca acuminataCocaine Local anaesthetic Erythroxylum coca (coca

plant)Deserpidine Antihypertensive Rauvolfia canescensDeslanoside Cardiotonic Digitalis lanata (Grecian

foxglove, woolly foxgloveL-Dopa Anti-parkinsonism Mucuna sp (nescafe, cowage)Emetine Amoebicide, emetic Cephaelis ipecacuanha

Glycyrrhizin Sweetener, treatment forAddison's disease

Glycyrrhiza glabra (licorice)

Gossypol Male contraceptive Gossypium species (cotton)Kheltin Bronchodilator Ammi visaga

Noscapine Antitussive Papaver somniferum (poppy)Papain Proteolytic, mucolytic Carica papaya (papaya)

Pilocarpine Parasympathomimetic Pilocarpus jaborandi(jaborandi, Indian hemp)

Podophyllotoxin Antitumor, anticancer agent Podophyllum peltatum(mayapple)

Quinidine Antiarrhythmic Cinchona ledgeriana (quininetree)

Rescinnamine Antihypertensive, tranquilizer Rauvolfia serpentina

Others8%

Nervous system6%

Antimutagens5%

Antimicrobial8%

Liver dysfunction4%Pain/Inflammation

8%

Gastro-intestinal12%

Diabetes mallitus13%

cardiovascular12%

Renal/Blood/Immune system

11%

Dermatology13%

Antimicrobial

Antimutagens

Nervous system

Others

Renal/Blood/Immunesystemcardiovascular

Diabetes mallitus

Dermatology

Gastro-intestinal

Pain/Inflammation

Liver dysfunction

The Indian Scenario: Ayurveda in 21st Century

Natural Products (Plants, Minerals, Animal) : Principle Tools of Traditional Healthcare System

“Ayurveda” The Science of Life

Traditional Medical Paradigms Sophisticated Helathcare Systems

Channelizing Ancient Knowledge for Modern Approach to Drug Discovery

Ethnopharmacological Approach•Study on Drug Actions; based on Cultural or Traditional use

•Multi-target guided Drug Discovery

Future Prospects: Will the Natural Products be still relevant in Drug Discovery for Future?

Frequent Isolation of Known Molecules

Length of Time Required for Characterization

Generation of Analogues from Complex Chemical Templates

Growing Advancement in the field of Chemistry & Biology

Identification of Proteins associated with onset of Diseases

Molecular targets for Screening: High Throughput tools

Speeding up the Drug Discovery

Conclusions

Linking of Indigenous Knowledge to Modern Research Activities

: More Effective Rate of Drug Discovery

Investigating Traditional Medicines with modern theories and

Techniques: Absorbing new ideas and concepts from

Traditional systems

Tapping the world’s Biodiversity for new Biological Activity

Natural Products made more User Friendly, i.e. reliably and

consistently supplied