NEW DRUG DISCOVERY FROM NATURAL PRODUCTS

LOGO

….end of an era or an endless

frontier?

SANDIP DAVE & MRUDANG THAKOR

INDUBHAI PATEL COLLEGE OF PHARMACY &
RESEARCH CENTER- DHARMAJ
TRADITIONAL NATURAL DRUGS….
NATURAL PRODUCTS..

MICROBIAL
WORLD

PLANT ANIMAL
KINGDOM SOURCES

SOURCES

VENOMS MARINE
& TOXINS WORLD
Why Natural Products…?

1 Structural diversity

2 Apparently’ unlimited quantity

3 Evolution against challenges

4 Potency

5 Safety , Efficacy Etc…

But Still.. We Are At…!
8% Are….

Small-molecule NCEs 1981-2002

Series1, natural
products, 6, 6%
ANTIBACTERIALS: 78%
ANTICANCER: 74%
Series1, natural
Series1, other, 39, 39% product
derivatives, 27,
27%

Series1, natural
product mimic, 23,
23%
Series1, synthetic
compounds with NP
pharmacophores, 5,
5%
natural products
natural product derivatives
synthetic compounds with NP pharmacophores
natural product mimic
other
 What’s The Reason….
 Herbal medicines contain a large variety of different
compounds.
 Several of these may have biological activity, but there is a
significant risk of side effects and toxicity. The active principle
present in small amount, so herbals are expected to be less
active than pure compound.
 Herbal medicines may be interacting with prescribed
medicines and there is no regulations or control of this matter
and their uses.
 BUT IT IS AN IMPORTANT LEAD TO DISCOVER AND DESIGN NEW DRUGS.
For Example…

Not All Ginseng Is The Same:

Rg1 (sterol ginsenoside) Rb1 (sterol ginsenoside)

Glucocorticoid receptor Estrogen receptor

upregulates a
growth receptor different pathway

stimulates blood vessel growth inhibits blood vessel growth

BUT IT IS AN IMPORTANT LEAD TO DISCOVER AND DESIGN NEW DRUGS

Our Aim….

SELECTIVITY STANDERED TARGET

&TIME
Common Procedure…

Marketing
1 to 2 Years
Approval Process

3 to 4 Years
Clinical Trials

5 to 6 Years
Development

3 to 9 Years
Research

Average 9 to 15 Years…!!
Time is money …..!

Cost control by time-oriented development

1 year 1000.000.000 $
1 month 83.333.774 $
1 week 19.230.770 $
1 day 2.739.726 $
1 hour 114.120 $
1 minute 1.902 $
1 second 31,70 $

By accelerated development saved $:

Basic Steps…
Chemical Library…

Selection of Hits….!!
Time and
Lead Finding Procedure…!! Money….!!!

Screening And Structure Illucidation…!

Preclinical studies…!!

Drug Discovery…!!

Clinical Trials,development…!!
New Drug Discovery From Natural Products….

Pre knowledge…

Collect source..
Crude Extracts..

Screening…
Separation: HPLC,HPTLC,GC…

Library.…
Finding Lead Molecule…
Structure Identification…

New Drug Discovery And Development…

Clinical Trials .. Phase 1,2,3

Approval Procedure.. Marketing…Phase 4

We Need….

Cost control by time-oriented development

By accelerated development saved $:

 Finding drugs……..

LEAD OPTIMIZATION

HITS-TO-LEAD
It is necessary to
IDENTIFYING HITS optimize the leads
The hits are properties: i.e.
further examined toxicity, potency,
in order to find binding strength,
AT This Stage A Lot ...
Of Compounds Are some
Tested Against The promising drug These
Target Protein. candidates – the modifications
Compounds Showing so-called leads. results in 10-500
Chemical Activity
Typically 1-3 lead lead variations
Against The Target sent for pre-
Are Promoted To Hits. compound series
are found. clinical testing..
Screening A
Library With E.G.
1,000,000 Compounds
May Result In 100-500
Hits.
In Vivo…Study…..

IN VIVO TESTS
• More expensive
• May cause suffering to animals
• Results may be clouded by interference with other biological
systems

About 2.6m animals/y used in

procedures in UK (11.6m in Europe)
Please…..Follow…

REFINEMENT

3R

REPLACEMENT REDUCTION
 Methods…
High Throughput Screening used to search large compound libraries
IDENTIFYING
HITS · Molecular Docking · QSAR · Pharmacophore Mapping
These methods can be used for Virtual Screening.

High Throughput Screening for validation runs.

Hits-To-Lead Laboratory experiments for confirmation and investigation of binding pro.

· Molecular Docking · QSAR · Pharmacophore Mapping

LEAD Laboratory experiments for testing the optimized leads.

OPTIMIZATION ·
Three must………………….

QSAR

Basic
concepts

HTS
Combinatorial
Chemistry
 What Is HTS ?
Biochemical target

Test many compounds

Compounds with desired effect
on target = Hit

 OR 
 

Hit directly Hit provides

used as structure for
chemical chemists to begin
probe to study developing a drug
target or other product
HTS and Technology…..

Robotics
Miniaturization
Sophisticated Assay Chemistry
Sophisticated Software and Database
HTS Contd…

Examples
of Assays:
What is QSAR?
A QSAR is a mathematical relationship
between a biological activity of a
molecular system and its geometric
and chemical characteristics.
QSAR attempts to find consistent
relationship between biological activity
and molecular properties, so that these
“rules” can be used to evaluate the
activity of new compounds.
Why QSAR?

The number of compounds required for

synthesis in order to place 10 different
groups in 4 positions of benzene ring is 104
Solution: synthesize a small number of
compounds and from their data derive rules
to predict the biological activity of other
compounds.
Compounds + biological
activity

QSAR

New compounds with

improved biological
activity
For Example….

hydrophobic (blue) and hydrophilic (red)

surface area of diazepam.
Don’t wait…Selection Source…

Microbial
Animals

Plants
Marine

Venoms
Combinatorial Chemistry…

Combination Hits..

M7
Few Examples…..

O
CH3 O

CH3 H
OH H3C
H3C H OH
O O O
HO H O
H3C OH OH O
OH CH3
Digitoxin
CH3 H
OH H3C
H3C H OH
O O O
HO H
H3C OH
OH
Digoxin
 OCH3 OCH3
H
OH H N
H
N
OH
N H N
Quinidine Quinine

MeO
N
N H
H H
O
H OCH3
MeOOC O
OCH3 OCH3
Reserpine OCH3
 HO O HO _
COO
O OH
R
H3C H3C
O O
CH3 CH3
CH3 CH3

R HO

Mevastatin R1 = R2 = H Pravastatin
Lovastatin R1 = H; R2 = CH3
Simvastain R1 = R2 = CH3
 O O O O O O

CH3
*
OH O OH OH

Warfarin Dicoumarol

_ _ _ _
CH2OSO3 COO CH2OH CH2OSO3 CH2OSO3
O O O O_ O O_ O
OH OH OH COO OH COO OH
OH OH
O O O O O O O
_ _ _ _
NHSO3 OH NHSO3 OSO3 NHCOCH3 OH NHSO3

Heparin
 So….

It’s not END of an ERA but…..ENDLESS FRONTIER….!!!

LOGO www.themegallery.com

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