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

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