LOGO NEW DRUG DISCOVERY FROM NATURAL PRODUCTS
SANDIP DAVE & MRUDANG THAKOR
INDUBHAI PATEL COLLEGE OF PHARMACY &
RESEARCH CENTER- DHARMAJ
….end of an era or an endless
frontier?
TRADITIONAL NATURAL DRUGS….
SOURCES
PLANT
KINGDOM
MICROBIAL
WORLD
ANIMAL
SOURCES
VENOMS
& TOXINS
MARINE
WORLD
NATURAL PRODUCTS..
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…!
Series1, natural products, 6, 6%
Series1, natural product
derivatives, 27, 27%
Series1, synthetic compounds with NP pharmacophores, 5,
5%
Series1, natural product mimic, 23,
23%
Series1, other, 39, 39%
Small-molecule NCEs 1981-2002
natural products
natural product derivatives
synthetic compounds with NP pharmacophores
natural product mimic
other
ANTIBACTERIALS: 78% ANTICANCER: 74%
8% Are….
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.
Glucocorticoid receptor
Rg1 Rb1
Estrogen receptor
upregulates a
growth receptor
stimulates blood vessel growth inhibits blood vessel growth
different pathway
Not All Ginseng Is The Same:
(sterol ginsenoside) (sterol ginsenoside)
For Example…
BUT IT IS AN IMPORTANT LEAD TO DISCOVER AND DESIGN NEW DRUGS
Our Aim….
SELECTIVITY STANDERED TARGET
&TIME
Common Procedure…
1 to 2 Years
3 to 4 Years
5 to 6 Years
3 to 9 Years
Approval Process
Clinical Trials
Development
Research
Marketing
Average 9 to 15 Years…!!
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 $
Time is money …..!
By accelerated development saved $:
Cost control by time-oriented development
Basic Steps…
Time and
Money….!!!
Chemical Library…
Selection of Hits….!!
Lead Finding Procedure…!!
Screening And Structure Illucidation…!
Preclinical studies…!!
Clinical Trials,development…!!
Drug Discovery…!!
New Drug Discovery From Natural Products….
Crude Extracts..
Separation: HPLC,HPTLC,GC…
Screening…
Structure Identification…
Library.…
Clinical Trials .. Phase 1,2,3
Approval Procedure.. Marketing…Phase 4
Finding Lead Molecule…
New Drug Discovery And Development…
Pre knowledge…
Collect source..
Cost control by time-oriented development
By accelerated development saved $:
We Need….
Finding drugs……..
HITS-TO-LEAD
LEAD OPTIMIZATION
IDENTIFYING HITS
AT This Stage A Lot
Of Compounds Are
Tested Against The
Target Protein.
Compounds Showing
Chemical Activity
Against The Target
Are Promoted To Hits.
Screening A
Library With E.G.
1,000,000 Compounds
May Result In 100-500
Hits.
The hits are
further examined
in order to find
some
promising drug
candidates – the
so-called leads.
Typically 1-3 lead
compound series
are found.
It is necessary to
optimize the leads
properties: i.e.
toxicity, potency,
binding strength,
...
These
modifications
results in 10-500
lead variations
sent for pre-
clinical testing..
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…
REPLACEMENT REDUCTION
REFINEMENT
3R
Methods…
IDENTIFYING
HITS
High Throughput Screening used to search large compound libraries
· Molecular Docking · QSAR · Pharmacophore Mapping
These methods can be used for Virtual Screening.
Hits-To-Lead High Throughput Screening for validation runs.
Laboratory experiments for confirmation and investigation of binding pro.
· Molecular Docking · QSAR · Pharmacophore Mapping
LEAD
OPTIMIZATION
Laboratory experiments for testing the optimized leads. ·
Three must………………….
Basic
concepts
QSAR
HTS
Combinatorial
Chemistry
What Is HTS ?
Biochemical target
Test many compounds
Compounds with desired effect
on target = Hit
OR
Hit directly
used as
chemical
probe to study
target
Hit provides
structure for
chemists to begin
developing a drug
or other product
Robotics
Miniaturization
Sophisticated Assay Chemistry
Sophisticated Software and Database
HTS and Technology…..
Examples
of Assays:
HTS Contd…
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
New compounds with
improved biological
activity
QSAR
hydrophobic (blue) and hydrophilic (red)
surface area of diazepam.
For Example….
Plants
Microbial
Animals
Marine
Venoms
Don’t wait…Selection Source…
Combinatorial Chemistry…
M7
Combination Hits..
Few Examples…..
CH3
CH3
O
O
OH
H
H
HOOOHO
OH
H3C
H3C
OH H3C
OH
CH3
CH3
O
O
OH
H
H
HOOOHO
OH
H3C
H3C
OH H3C
OH
OHDigitoxin
Digoxin
N
N
HOH
OCH3
H N
N
OCH3
H
H
OH
Quinidine Quinine
NH
N
H H
H
MeOOC
OCH3
O
OOCH3
OCH3
OCH3
MeO
Reserpine
O
CH3
OOH
R
OCH
3
R
CH3
OH
COO
CH3
OH
OH
OCH
3
CH3
_
Mevastatin R1 = R2 = H
Lovastatin R1 = H; R2 = CH3
Simvastain R1 = R2 = CH3
Pravastatin
O O
OH
CH3
O
O O
OH
OO
OH
*
Warfarin Dicoumarol
O
OH
OH
O
COO
O
O
CH2OH
NHSO3
OH
O
O
CH2OSO
3
NHSO3
OH
O
OH
OH
O
COOO
O
CH2OSO
3
NHSO3
OH
O
OSO3
OH
O
COOO
O
CH2OSO
3
NHCOCH3
OH
_
_
_
_
_
_
_
_ _
_
Heparin
So….
It’s not END of an ERA but…..ENDLESS FRONTIER….!!!
LOGO www.themegallery.com
Add your company slogan