Transcript INTRODUCTION - IGMORIS - Indian GMO Research Information

New Drug Discovery From Medicinal
Plants/ Natural Products
Dabur Research Foundation, Sahibabad
Natural Products as a part of Traditional Medicinal System
Ancient Egyptian,
Literature
Chinese,
and
Indian
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
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
The Empirical Approach
cultures and systems of medicine.
Understandings of a relevant physiological process. Often
andaEphedrine
developse.g.Morphine,
a therapeutic Quinine
agent from
naturally occuring lead
The Molecular Approach
molecule.
Availability
or understanding of a molecular target for the
e.g.Tubocurarine
and other muscle relaxants, Propranolol
medicinal
agent.
and other
β-adrenoceptors
Majority
of drug
discovery antagonists,
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
Traditional medicinal uses of Natural
Products
Chemical Libraries
Historical Compound Collection
Natural Product Libraries
Impirical understanding of Physiology
Combinatorial Libraries
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
 Combinatorial Chemistry
•
Peptides and Oligonucleotide libraries
•
Small drug-like molecules
 Natural Product Libraries
High Throughput Screening
100,000 /day
•
Greater chemical/ Structural Diversity
•
Natural Products are relatively smaller
(>1000Da)
New Chemical Entities Organized by Source/Year
1
7
0
5
1
2
2
1
3
4
Number of NCEs
6
3
2
2
1
5
8
8
5
4
8
13
9
12
9
8
0
4
7
14
2
2
S*
6
9
12
8
1
3
10
1
NM
S
5
0
12
12
6
V
5
0
0
13
9
7
1
3
2
3
15
12
7
1
10
14
10
4
5
14
18
2
6
8
6
2
3
ND
N
12
8
0
2
12
8
1
20
8
B
5
8
2
3
8
8
4
2
3
2
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Year
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
S*
4%
V
3%
B
B
12%
N
N
5%
NM
20%
ND
S
NM
S*
V
ND
23%
S
33%
•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
Early 90s
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
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
Natural Products as Sources of New drugs…...
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
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.)
•Morphine
(Papaver somniferum)
Anabolic steroids, Antiinflammatory, Oral Contraceptives
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
Source
Acetyldigoxin
Cardiotonic
Aesculetin
Arecoline
Asiaticoside
Betulinic acid
Caffeine
Antidysentery
Anthelmintic
Vulnerary
Anticancerous
CNS stimulant
Camptothecin
Cocaine
Anticancerous
Local anaesthetic
Deserpidine
Deslanoside
Antihypertensive
Cardiotonic
L-Dopa
Emetine
Glycyrrhizin
Anti-parkinsonism
Amoebicide, emetic
Sweetener, treatment for
Addison's disease
Male contraceptive
Bronchodilator
Antitussive
Proteolytic, mucolytic
Parasympathomimetic
Digitalis lanata (Grecian
foxglove, woolly foxglove)
Frazinus rhychophylla
Areca catechu (betel nut palm)
Centella asiatica (gotu cola)
Betula alba (common birch)
Camellia sinensis (tea, also
coffee, cocoa and other plants)
Camptotheca acuminata
Erythroxylum coca (coca
plant)
Rauvolfia canescens
Digitalis lanata (Grecian
foxglove, woolly foxglove
Mucuna sp (nescafe, cowage)
Cephaelis ipecacuanha
Glycyrrhiza glabra (licorice)
Gossypol
Kheltin
Noscapine
Papain
Pilocarpine
Podophyllotoxin
Quinidine
Rescinnamine
Antitumor, anticancer agent
Antiarrhythmic
Antihypertensive, tranquilizer
Gossypium species (cotton)
Ammi visaga
Papaver somniferum (poppy)
Carica papaya (papaya)
Pilocarpus jaborandi
(jaborandi, Indian hemp)
Podophyllum peltatum
(mayapple)
Cinchona ledgeriana (quinine
tree)
Rauvolfia serpentina
The Indian Scenario: Ayurveda in 21st Century
Pain/Inflammation
8%
Liver dysfunction
Antimicrobial
4%
8%
Antimutagens
5%
Nervous system
6%
Antimicrobial
Antimutagens
Nervous system
Others
Gastro-intestinal
12%
Others
8%
Renal/Blood/Immune
system
cardiovascular
Diabetes mallitus
Dermatology
Gastro-intestinal
Pain/Inflammation
Dermatology
13%
Diabetes mallitus
13%
Liver dysfunction
cardiovascular
12%
Renal/Blood/Immune
system
11%
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