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1. SEMINAR ON COMBINATORIAL CHEMISTRY IN DRUG
DISCOVERY
Presented By
DIXHU RAJ DIXIT
M.Pharm Pharmacology 2ND semester
Enrollment-ADTU/2021-23/MPS/007
Submitted To
DR.MANASH PRATIM PATHAK
Assistant Professor, Faculty of Pharmaceutical Science, Adtu

2. CONTENT
 INTRODUCTION
 APPLICATION
 ADVANTAGES AND DISADVANTAGES
 IMPORTANCE OF COMBINATORIAL SYNTHESIS
 IDEAL CRITERIA FOR COMBINATORIAL CHEMISTRY
 DESIGN OF COMBINATORIAL CHEMISTRY
 RECENT FUTURE PROSPECT
 CONCLUSION

3. Combinatorial chemistry
 Definition
Combinatorial chemistry is a technique by which large numbers of different
but structurally similar molecules are produced rapidly And submitted for
pharmacological assay(potency of drug).
This technique uses the same reaction conditions with the same reaction
vessels to produce a large range analogous(Comparable).
Technique invented in the late 1980s and early 1990s to enable tasks to
be applied to many molecules simultaneously.
 Combinatorial Library:
The products produced from combinatorial synthesis are known as a
combinatorial library.
Libraries may be a collection of individual compounds or mixtures of
compounds.

5. Application:
 Applications of combinatorial chemistry are very wide.
Scientists use combinatorial chemistry to create large
population of molecules that can be screened efficiently(protect
well organised).
 Provides a stimulus for robot-controlled and immobilization
strategies(long term reduced) that allow high-throughput and
multiple parallel approaches to drugdiscovery.

6. Advantages:
Fast
Combinatorial approach can give rise to million of compound in same time as it will
take to produce one compound by traditional method of synthesis.
Economical
A negative result of mixture saves the determine of synthesis, purification &
identification of each compound.
Easy
Isolation, purification & identification of active molecule from combinatorial
library is relatively easy.
Drug Discovery
Mixed Combinatorial synthesis produces chemical pool. Probability of finding a
molecule in a random screening process is proportional to the number of molecules
subjected to the screening process.
Drug Optimization
Parallel synthesis produces comparable with slight differences which is required
for lead optimization.

7. Disadvantages:
 Efficiency is highly affected by compound's size, solubility and
function group.
 Compounds produced tend to be Achiral of Racemic(mirror image).

8. Importance of Combinatorial Synthesis in Medicinal
Chemistry
The need to find new lead compound in
drug discovery has been the major driving
force(Catalyst) in the development of
Combinatorial synthesis.
By Combinatorial synthesis it is possible to
screen over a million of compounds for
around hundred targets per year to find
lead compound.

10. Basic concept of combinatorial chemistry
 Preparation of large number of different compounds at the same
time.
 High throughput –screening provides the most promising
(sucessful)substances.
 Conventional Reaction: A + B  A-B
 Combinatorial Reaction: A(1-n)+B(1-n)  A(1-n)-B(1-n)
 Combinatorial chemistry as a very useful in drug discovery and
material science.

12. Ideal criteria for combinatorial synthesis
The reactions used when designing a combinatorial sequence should
ideally satisfy the following criteria:
1. The reactions should be specific, relatively easy to carry out and give a
high yield.
2. The reactions used in the sequence should allow for the formation of a
wide range of structures for the final products as possible, including all
the possible stereoisomers.
3. The reactions should be suitable for use in automated equipment.
4. The building blocks should be readily available.
5. It must be possible to accurately determine the structures of the final
products.

13. The design of combinatorial syntheses
 Two general strategies may be followed when designing a
combinatorial synthesis.
 Linear synthesis: In this case the building blocks are
successively added to the preceding structure so that it
grows in only one direction.
 Template synthesis: This type of synthesis can proceed in
different directions from an initial building block known
as a template provided that the template has either the
necessary functional groups or they can be generated
during the course of the synthesis.

14. Fig: (a) Linear synthesis. The sequential attachment of building blocks.
(b) Template Method. The non-sequential attachment of building blocks using
B as a template

15. 1. SOLID PHASE TECHNIQUES
• Reactants are bound to a polymeric surface and modified whilst still attached.
• Final product is released at the end of the synthesis.
1.1 Advantages
 Specific reactants can be bound to specific beads(interaction to spherical particle)
 Products formed are distinctive for each bead and physically distinct.
 Excess reagents can be used to drive reactions to completion.
 Excess reagents and by products are easily removed.

16. Disadvantage
 Optimal reaction conditions for solid phase synthesis can be
difficult to determine, and developing these are far more time
consuming than the actual reactions will be.
 There is limited the range of chemistry available for attachment to
the resins in solid phase.

17. 1. Solid support
Swelling Starting material,
reagents and solvent
Linkers
 Beds must remain stable.
 Most reactions occur in the bead interior.
Resin bead
Solid support:(spherical particle inner)

18. 1.1Anchor or linker
 A molecular moiety which is covalently attached to the solid
support, and which contains a reactive functional group.
 Allows attachment of the first reactant.
 The link must be stable to the reaction conditions in the
synthesis but easily cleaved to release the final compound.
 Different linkers are available depending on the functional group
to be attached and the desired functional group on the product.
 Resins are named to define the linker
e.g. Merrifield, Wang, Rink

19. Linking functional group
Linker
O
D
i hydropyran
deri vati sed resi n
O
B
ead
O
L
i n
ker
Dihydropyran resin
Linking functional group
Linker
Cl
Cl
B
ead Li nker
Ar
Ar
Cl
Barlow's resin

20.  Each tea bag contains beads and is labelled.
 Separate reactions are carried out on each tea bag.
 Combine tea bags for common reactions or work up procedures.
 A single product is synthesised within each tea bag.
 Different products are formed in different tea bags.
 Economy of effort - e.g. combining tea bags for workups.
 Cheap and possible for any lab.
 Manual procedure and is not suitable for producing large
quantities of different products.
2. Parallel Synthesis
2.1 Houghton’s Tea Bag Procedure

21. 2. Parallel Synthesis
2.2 Automated parallel synthesis Wells
• Automated synthesisers are available with 42, 96 or
144 reaction vessels or wells.
• Use beads or pins for solid phase support.
• Reactions and work ups are carried out
automatically.
• Same synthetic route used for each vessel, but
different reagents.
• Different product obtained per vessel.

22. ETC
2. Parallel Synthesis
Automated parallel synthesis of all 27 tri peptides from 3 amino acids

23. 27 TRIPEPTIDES
27 VIALS
2. Parallel Synthesis
Automated parallel synthesis of all 27 tripeptides from 3 amino acids

24. Glycine (Gly)
Alanine (Ala)
Phenylalanine (Phe)
Valine (Val)
Serine (Ser)
25 separate
experiments
Gly-Gly
Gly-Ala
Gly-Phe
Gly-Val
Gly-Ser
Ala-Gly
Ala-Ala
Ala-Phe
Ala-Val
Ala-Ser
Phe-Gly Val-Gly Ser-Gly
Phe-Ala Val-Ala Ser-Ala
Phe-Phe Val-Phe Ser-Phe
Phe-Val Val-Val Ser-Val
Phe-Ser Val-Ser Ser-Ser
3. Mixed Combinatorial Synthesis
Combinatorial procedure involves five separate syntheses
using a mix and split strategy
The Mix and Split Method
Example
- Synthesis of all possible dipeptides using 5 amino acids
•Standard methods would involve 25 separate syntheses

25. Solution Phase Technique
 When combinatorial chemistry first emerged, the initial focus was on solid-
phase approaches due to the many advantages.
 Solution chemistry was not regarded as being suitable for combinatorial
chemistry because of the often tedious isolation and purification.
 It was first used for easily synthesized compound classes [amides,
sulfonamides, urease, heterocyclic (thiazide)].
 Presently, solution-phase combinatorial synthesis is attracting more interest
because of some advantages.

26. Advantages
 Many more reactions are optimized in solution-phase.
 All reactive groups of the starting materials are available.
 No limitations of the thermal or chemical stability of the resin.
 Synthesis is shorter by one or two steps.
 Reactions in solution often need considerably less time.
 Reactions that involve insoluble components are confined to solution phase.
 Reactions can be followed conveniently by simple means (TLC, NMR, UV).
 In general, the reaction volumes in relation to the amount of product are smaller.

28. RECENT FUTURE IMPACT
 Combinatorial chemistry technology has revolutionized the way
drug companies discover new leads. Because the technology is so
powerful, it has been quickly embraced by the large pharmaceutical
companies such as American Home Products.

29. CONCLUSION
 Combinatorial chemistry has accelerated the development of a
whole set of combinatorial tools comprising combinatorial
library design, efficient synthetic methods, reagents for library
synthesis (including solid supported reagents), linkers, bilayer
beads, library encoding and decoding strategies, HTS methods
and equipment, and soon.

30. REFERENCE
 Geysen HM, Meloen RH, Barteling SJ: Use of peptide synthesis to probe viral
antigens for epitopes to a resolution of a single amino acid. Proc. Natl. Acad. Sci.
U. S. A. 1984, 81:3998-4002.
 Houghten RA: General-method for the rapid solid-phase synthesis of large
numbers of peptides—specificity of antigen–antibody interaction at the level of
individual aminoacids. Proc. Natl. Acad. Sci. U. S. A. 1985, 82:5131-5135.
 Lam KS, Salmon SE, Hersh EM, Hruby VJ, Kazmierski WM, Knapp RJ: A new type
of synthetic peptide library for identifying ligand-binding activity. Nature 1991,
354:82-84
 Houghten RA, Pinilla C, Blondelle SE, Appel JR, Dooley CT, Cuervo JH:
Generation and use of synthetic peptide combinatorial libraries for basic
research and drug discovery. Nature 1991, 354:84-86.
 Bunin BA, Ellman JA: A general and expedient method for the solid-phase
synthesis of 1,4-benzodiazepine derivatives. J. Am. Chem. Soc. 1992, 114:10997-
10998.

31. THANK YOU