1. Combinatorial chemistry

2. contents combinatorial chemistry History of combi-chem
Principle of combi-chem
Synthetic methods
a)solid phase synthesis,
b) solution phase synthesis,
Screening methods
Application
Conclusion
Bibliography

3. COMBINATORIAL CHEMISTRY
Combinatorial chemistry (or CombiChem) is an innovative method of synthesizing many different substances quickly and at the same time. Combinatorial chemistry contrasts with the time-consuming and labor intensive methods of traditional chemistry where compounds are synthesized individually, one at a time.
CombiChem is used to synthesize large number of chemical compounds by combining sets of building blocks. Each newly synthesized compound's composition is slightly different from the previous one.

4. History of combi-chem
-> Although combinatorial chemistry has only really been taken up by industry since the 1990s, its roots can be seen as far back as the 1960s when are searcher at Rockefeller University, Bruce Merrifield, started investigating the solid-state synthesis of peptides
-> Bruce Merrifield won the Nobel prize in chemistry in 1984 for his work on solid-phase synthesis.

5. Principle: Used extensively in relation with drug discovery
Principle of Combinatorial Chemistry:
-> Generation of Compound Libraries from Molecular Building blocks which are usually used in high-throughput screening.
HTS
Library

6. How does combinatorial chemistry differ from traditional methods
In contrast to this approach, combinatorial chemistry offers the potential to make every combination of compound A1 to An with compound B1 to Bn.

7. Synthetic methodologies for production of combinatorial libraries
Solid phase synthesis
the compound library have been synthesized on solid phase such as resin bead , pins or chips.
b) solution phase synthesis
In this method synthesis of compounds takes place in solution phase.

8. A simple model Take some beads made from a polymer
React the beads with a group called a linker
3. Mix the bead in with an alcohol that you want to use in a chemical reaction. The linker will bind to it and hold it on the bead.

9. A simple model
Have 6 reaction vessels each containing a different acyl chloride. Put a 1/6 of your beads into a mesh bag and put into a container.

10. A simple model Esterification occurs forming 6 different esters.
6. The beads are removed from the vessel by lifting up the mesh bag. They are washed to remove any unreacted acyl chloride

11. A simple model 7. A reaction is used to break the linker group down.
8. The polymer beads are reused
9. You have made 6 different esters which can now be tested for biological activity

12. A simple model
10. How many esters would you have made if you had attached 6 different alcohols to the beads?

13. Solid phase synthesis. Introduction
Organic reaction that carried out on solid support / substrate that are covalently attached to a polymeric resin

14. RECENT EXAMPLES - Epothilone A - Radiolabeled biotinylated peptide
substrate - Human big gastrin2 and cholecystokin - Dipeptide mimetic - Phosphopeptide thioesters

15. Advantages of solid phase synthesis over traditional synthesis.
1. Over all process is quick.
2. Purification of each product can be achieved in one step.Only purification technique is filtration.
3. Purification in each step is possible.
4. Synthetic intermediates don’t have to be isolated.
5. Can be automated with robots.

16. Disadvantages of solid phase synthesis
1.High chemical consume.
2.Expensive.
3.Low reaction rates.
4.Special substrates needed.
5.Extra labor required to develop solid phase route.
6.Yields can be low and produces very few molecule at a time for testing.

17. Preparation of Libraries
Combinatorial Chemistry
Preparation of Libraries
Parallel Synthesis
Each compund is prepared in a specific vessel (on pins or Tea- bags)
Array of reaction vessels (96 well plates -> each well other compound)
Automated control of reactions -> easy to keep track of each compound
High yields
Useful for epitope mapping
Just applicable when small number of positions are being varied -> small libraries

18. Analytical equipments used in combi-chem
HPLC – it is used to separate the compounds of combinatorial libraries
UV-spectrophotometry
IR- spectrophotometry
Hypenated techniques such as HPLC-MS etc

19. Screening methods
Screening is a process by which the biologically active compounds are identified among a mixture of chemical compounds
The screening methods are
High-throuhput screening,
Virtual screening.

20. CADD methods (COMPUTER AIDED DRUG DESIGN)
To examine, evaluate and compare complex molecular structure
To modify structure and assess geometric and energetic consequences of such modifications
To perform conformational analysis
To build macromolecules

21. Applications Mainly it is applied in the discovery of drugs
Eg: RALOXIFN
To synthesis analogues of existing lead molecules to elucidate the SAR.
Preparation of hydrazones and discovery of anti biotic compounds synthesis.

22. CONCLUSION:
Combi-chem had revolutinized drug research by enabling a dramatic reduction in development time (4-7 years) by speeding abd identification of lead compound.
Combi-chem can reduce the required for drug discovery from its current average of 4 to 1 year.

23. Bibliography
Donald.J.Abraham, Burgers medicinal chemistry and drugs discovery, vol-2, sixth edition, pg.no-1-69.
Thomas.L.Lemke, David.A.Williams, Foyes principles of medicinal chemistry, sixth edition,pg no
K.Ilango, P.Valentina, Text book of medicinal chemistry , sixth edition, pg. no
Ramarao nadendla, Medicinal chemistry, Revised edition, pg no

24. Thank You