USEFUL METHOD FOR LEAD IDENTIFICATION IN DRUG DISCOVERY PROCESS.

1. COMBINATORIAL
CHEMISTRY
Name of student : PUJA R. BHALERAO
Class : M.Pharm ( Sem-II)

2. CONTENT
• Definition
• Introduction
• Principle of Combinatorial Chemistry
• Approaches of Combinatorial Chemistry
• Combinatorial Library
• Types of Combinatorial Library
• Methods of Combinatorial Chemistry
• Techniques of Combinatorial Chemistry
• Advantages of Combinatorial Chemistry

3. Definition
combinatorial chemistry is a technique by which
large number of different but structurally similar
molecules are produced rapidly and submitted for
pharmacological assay.

4. INTRODUCTION
It is widely accepted that combinatorial chemistry was born in the early 1980s.
By accelerating the process of chemical synthesis, this method is having a profound
effect on all branches of chemistry, but especially on drug discovery.
Focused on the preparation of chemical libraries for the generation of new lead for
drug discovery.
To reduce the time and cost associated with producing effective and competitive new
drugs.

5. PRINCIPLE
• The basic principle of combinatorial chemistry is synthesizing large number of
different compounds at the same time Instead of synthesizing compounds in a
conventional one at a time manner and then to identify the most promising
compound for further development.

7.  Orthodox synthesis:
In orthodox synthesis , there is a stepwise-directed synthesis of
one specific product using basic fundamentals of organic chemistry.
A + B C

9. Combinatorial chemistry:
In contrast to this approach, combinatorial chemistry offers the
potential to make every combination of compound A1 to An with compound B1 to
Bn.

11. COMBINATORIAL APPROACHES
Creating chemical
libraries.
Identification of
active ingredients.

12. CHEMICAL LIBRARIES
Collection of finally synthesized
compounds.
These chemical libraries are simple in terms
of a series of excessively stored chemicals.
Each stored chemical has associated
information such as the chemical structure,
physiochemical characteristics, purity,
quantity of the compound .

13. CHEMICAL LIBRARIES

14. Scaffold-based
Libraries
Backbone-
based Libraries
Types of chemical libraries:

15. Core-structure, which is common
to all compounds of the library.
Several single building blocks can
consist of Scaffold or by a common
backbone.
In both case, the accessible
dissimilarities of compounds
within the library depend on the
building blocks which are used for
the construction.

16. Scaffold libraries:
Example- Amino acid and Amino
Benzophenone.

17. Backbone libraries:
Example : Nucleic acid and
Carbohydrate.

18. METHODS OF COMBINATORIAL
SYNTHESIS
Solid phase combinatorial
chemistry
(The compound library have been
synthesized on solid phase such as
resin bead)
Solution phase combinatorial
chemistry
(The compound library have
been synthesized in solvent in
the reaction flask)

19. Solid phase combinatorial chemistry
In solid phase combinatorial chemistry.
the starting compound is attached to an
insoluble resin bead.
Then reagents are added to the solution in
excess.
And the resulting products can be isolated
by simple filtration.
Then excess reagent is washed away.

20. Solid phase combinatorial chemistry

22. • The use of solid support for organic synthesis relies on three interconnected
requirements:
Polymeric solid support
A linker
Protecting group

24. • Polymeric solid support:
the choice of solid support depends on the type of chemistry of reaction.
In addition, resin used must be stable under all those reaction conditions.

25. • Linker :
The linker is the molecule that site between our compound and the solid
support .
The linker’s role is to keep our compound attached to the solid support
during synthesis and allows us to cleave off the final product in a high yield
under conditions that do not destroy the product.
The best linker must allow attachment and cleavage in quantitative yield.

26. • Protecting Group :
protecting groups are important for blocking and regenerating certain
functional groups in a reaction sequence .
TBOC : (tertiarybutyloxy carbonyl)
(Fluoromethoxy carbonyl benzyl ester )

27. Solution phase combinatorial chemistry
Reaction proceeds in Solution.
Can be used to produce libraries that consist
of single compounds or mixtures.
Single compound libraries are prepared
using parallel synthesis.
Easy characterization of intermediates as
well as end product.
Standard analytical protocols can be used to
characterize products between each reaction
step.

28. Solution phase combinatorial chemistry

30. Techniques of combinatorial chemistry
 In the process of new drug discovery . Combinatorial chemistry
has two basic techniques for creating chemical libraries.
Parallel synthesis method
Split and mix synthesis method

31.  Parallel synthesis method:
In separate vessels, different compounds are
synthesized (without re-mixing).
This is not like a split synthesis because it
requires a solid support.
It can be done without solid support or in a
solution. A 96 well micro titer plate is
commonly used format for parallel synthesis

34.  Advantages:
•Each compound is substantially „pure“in its location
•Defined location provides the structure of a certain compound
•Easier biological evaluation

35.  Split and mix method:
The starting material is split in ‘n’ portions.
Then reacted with ‘n’ building blocks And
recombined in one flask for the second step.
This procedure is repeated.
This method is particularly employed for solid
phase synthesis.

37. Advantages:
• Method of having choice for large libraries.
• Less reaction vessels required.

38. Advantages
• Rapid synthesis.
• Large number: A large diverse chemical library derived from combinatorial
synthesis provides a better chance for generating new leads .
• Richer data from screening: Medicinal chemists are guided through the
optimization process by SAR.
• Increased likelihood of success .
• Large combinatorial libraries allow researchers to document activity of a large
number of compounds.