1. Combinatorial Chemistry

2. Synthesis of many structures (diversity) combinatorial technology, combinatorial library molecular diversity What is Combinatorial Chemistry? A synthetic strategy which leads to a large set of compounds. Product of matrix chemistry (systematic synthesis ) Automation of synthesis (speed)

3. Why do we need Combinatorial Chemistry ? 1. From New Drug discovery --- biodiversity drug design 2. From Genome Project --- post-Genome Era more new drug targets

4. Issues : ! Human Diversity ----- Customized Drug ! Possible Targets ----- Too many Solutions for Lead Compound Search : 1. Existing Sample collection :a. Natural Sources scarce b. Drug Design lead to homogeneous & specific sets of compounds. 2. De Novo Design Too many unexpected & complicated synthesis 3. Combinatorial Chemistry Drug Development of 21st Century

5. Drug-like Compounds How Many We Want from Combinatorial Chemistry possible combination of drug like compounds : ~ 10 63 -64 synthesizable number of compounds : ~ 10 24 Practical number of compounds in a library : 10 6 with design < 10 3 with virtual screening, virtual library Solution (?) -- Combination of Design & Informatics

6. ’70 : Natural Products ’80 : Rational Design ’90 : Combi. Chem.& HTS ’00 : Information Guided Design Rational Design Diverse Design Serendipity 10 0 10 6 10 13 ( immune system) Paradigm Shift of Drug Development

7. 1. Nature does it all the time. -- can we mimic mother nature ? 2. Are there ways to automate the synthesis ? -- Immune System – Molecular Diversity -- Peptide synthesizer : 40 min./cycle -- DNA synthesizer : 1.5 min./cycle 3. Are there ways to generate many compounds at a time ? Combinatorial Chemistry

8. -- Peptide synthesizer : 40 min./cycle -- DNA synthesizer : 1.5 min./cycle Solid Phase Organic Synthesis solid phase synthesis : needs optimization for every new reaction Time required to develop a combinatorial chemistry : 6 - 24 months : Size of the combinatorial library Purpose of the library : General Library Lead Search SAR Construction Target Area

10. 1.Mixture Library a. SELEX -- nucleotide library --- 4 n b. Positional scanning -- peptide library --- 20 n c. Phage Display -- peptide library --- 10 8 d. Split- mix method ( bead tech.) -- general e. simple mixture Combinatorial Chemistry : Strategy

11. SELEX(Systematic Evolution of Ligands by Exponential Enrichment)

20. 2. Matrix Library a. Pin Technology b. Chip Technology c. Parallel Array synthesis Combinatorial Chemistry : Strategy

26. Multicomponent Reaction 1. Passerini reaction 2. Ugi reaction

27. Multicomponent Reaction 3. Hantzsch reaction