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RASOANAIVO Plants based Drug Discovery .pdf



Nom original: RASOANAIVO_Plants-based Drug Discovery.pdf
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IMRA weekly meeting

Plants-based Drug Discovery:
Basic background, recent results, new directions

Philippe Rasoanaivo
Biotherapeutics Laboratory
5 September 2008

NAPRECA Symposium,
Antananarivo, August 2005

“Natural products and drug discovery”

Drug discovery from African flora
NAPRECA Symposium
Kampala, July 2007

IOCD Symposium
Botswana, February 2008

Natural products: unlimited sources for the development of
drugs, cosmetics and foods

Trieste Conference on
“Drug design and discovery for developing countries”
(3-5 July 2008)

?
How to reduce the size of the haystack???

Random drug discovery
Random screen, HTS
Target identification

Biology

Combinatorial chemistry
Medicinal chemistry, Natural products

Chemistry

Bioinformatics, structural genomics
Virtual screening, Drug design

Rational drug discovery

Basis of drug design
Targets
(proteins)

Structure 3D

Molecules

?

?

Ligands

Strategies in drug design
■ No protein 3D

■ Protein 3D

structure,
■ No ligands

structure,
■ No ligands

Combichem, HTS
■ No protein 3D structure,
■ Ligands

Pharmacophores,
3D similarity,
3D QSAR

LBLD

De novo screening

■ Protein 3D structure,
■ Ligands
Structure-based
design

SBLD

Experimental high throughput screening
versus
Virtual screening
High Througput Screening:
- Cells or recombinant protein.
- Fluorescent or luminescent readout.
- Automated, miniaturized.

Virtual screening:
- Ligand-based: similarity search, 2D or 3D,
pharmacophore search, flexible 3D search.

- Structure-based: high throughput docking.
- Virtual or real librairies

COOH

HO

A Hit is no Ligand is no Lead is no Drug

Drug discovery and plants
Looking for innovative approaches
in terms of complementarities
► High throughput screening.
► Reverse pharmacognosy.
► Reverse pharmacology.

Pharmacognosy
versus
Reverse pharmacognosy
Pharmacognosy
1. Plants
2. Extracts
3. Biological tests
4. Bio-guided identification
5. Bioactive molecules

Reverse
pharmacognosy
1. Molecule database or
molecule library
2. Virtual screening or
biological tests
3. Knowledge-base
identification
4. Plants

O
O

OH

O
O

HO

O

Salacia leptoclada
IC50 = 95 ng/ml

HO
O

COOH

O

Maba quercina
IC50 = 118 ng/ml

O

HO

Gymnospria linearis

O

O

O

H
OH

21

Garcinia orientalis
IC50 = 1.2 µg/ml

R

O

O
O

From 2 Croton species of the deep South
IC50 = 126 ng/ml

Acetylcholinesterase inhibitors
Synthetic

Natural products

N

N

O

S

N
N

Acridone (Rutaceae)
N

Reverse
Pharmacognosy

S

N

O

O

Xanthone (Clusiaceae)
N
N

N

N

R

Indole alkaloids

R

Chikungunya
► Ethnobotany-oriented collecting
► Reverse pharmacognosy

N

N

Quinoline (Rutaceae)
HO

O
H3 CO

N

N

Quinine

Acridone (Rutaceae)

Reverse pharmacology in
ethnobotany-based drug discovery

Risk

Integrated approach

in homo
in vivo

in vitro cell-based
in enzymo
in silico
Conventional drug discovery

Value

Reverse pharmacology

Medicinal plants and
erectile and libido dysfunction
July 2004background
Historical
October 2004

May 2005

May 2006

Erectile
Mechanism
and libido
of erection
dysfunction
Brain stimuli
Visual
Olfactory
Tactile
Auditory
Fantasy

Vascular effects

Erection

Libido
Psychogenic
Anxiety
Strained relationships
Lack of sexual arousability
Depression, schizophrenia

Organic
Hypertension
Hyperlipidemia
Diabetes

Nervous stimuli

Release of
neurogenic NO

Vascular effects

GTP

Release of
endothelial NO

Guanylate cyclase
activation
PDE5

GMP

c.GMP
Increase in c.GMP
Viagra

Erection
No Nitric oxide = No erection

Vascular mechanism of erection

Antandroy

Mating behaviour test

Frequency mounting
Intromission
Ejaculation

O

O

O

O

O

O
O

O
O

O

O

O

O

O

O

O

O

O

O

O
O
O
O

O

O

OH

O
O

O

O

O

O
O

OH
O

OH
O

O

O

O

O

O

O

O

O

O

C

O

O
O

Milijaona et al.,
Phytochemistry 1999, 52, 1141

HO
O
O

OH

O

O

Neobeguin

Trans-esterification
O

O

O

O

O

O

O
O

O

O

OH

O
O

O

O

O
O

O

O

O

O
OH

OH
O

O

O

O

O

●NO
●O2

O2
NADPH oxidase

Oxydation
Nitration

ONOO OH
R'

HO

OH

O
R

2 Metabolites

OH
OH

Nitrate

Limonoids
Diterpenes

Flavonoids

Malaria and reverse pharmacology

Plant 01
Plant 02
Plant 03
Plant 04

In vivo
% inhibition
(100mg/kg)

Cytotoxicity
% inhibition
(10µg/ml)

67.2
58.0
48.2
35.4

25.2
17.5
10.6
15.9

New directions
Increasing life expectancy

Diseases of ageing
► Memory decline
► Alzheimer disease
► Erectile and libido dysfunction

Acknowledgments


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