1. Combinatorial Chemistry and Library Design
Chemical Informatics Lecture
Based largely on the C&EN story published October 27, 2003, pp. 45 ff.

2. Combinatorial Chemistry
Definition: the synthesis of chemical compounds as ensembles (libraries) and the screening of those libraries for compounds with desirable properties
Potentially speedy route to new drugs, catalysts, and other compounds and materials
Technique invented in the late 1980s and early 1990s to enable tasks to be applied to many molecules simultaneously

3. Combichem Techniques Tools Solid-phase synthesis Resins
Reagents (Monomers)
Linkers
Screening methods

4. Combichem Methods
Use of solid supports for peptide synthesis led to wider applications
Products from one reaction are divided and reacted with other reagents in succession
Split-mix scheme: library size increases exponentially

5. DIVERSE AND FOCUSED LIBRARIES
Many early disappointments led to:
Design of smaller, more focused libraries with much information about the target
May concentrate on a family of targets (e.g., proteases or kinases)
Use of more diverse libraries when little is known about the target
“Primary screening libraries
Give broad coverage of chemistry space
Selection of compounds with “drug-like” physicochemical properties

6. Problems with Early Combichem Libraries
Many compounds had undesirable properties:
Size
Solubility
Inappropriate functional groups

7. Criticism of the Technique
Early libraries often based on a single skeleton (basic structure)
Limited number of skeletons accessible
Individual library members were structurally similar
Compounds tended to be achiral or racemic
Initial emphasis on creating mixtures of very large numbers of compounds now out of favor

8. LIBRARY ENUMERATION
Process by which the molecular graphs of the product molecules are generated automatically from lists of reagents (using connection tables or SMILES strings)
Fragment marking – Central core template and one or more R groups
Reaction transform approach – Transform is a computer-readable representation of the reaction mechanism: atom mapping

9. Advantages/Disadvantages
Fragment marking generally a very fast enumeration once core template and R group fragments are defined.
May be difficult to generate the core and to generate fragments automatically

10. Combichem Techniques (cont’d)
Markush-based approaches to enumeration
Ideally suited when a common core can be identified
Certain subsets of the product structures may have features in common

11. COMBINATORIAL LIBRARY DESIGN STRATEGIES
Two Main Strategies:
Monomer-based selection:
Subsets of monomers selected without consideration of the products
Product-based selection:
Properties of the resulting product molecules influence the selection of the monomers
Much more computationally demanding than monomer-based selection, but can be more effective when wanting to optimize the properties of a library as a whole

12. APPROACHES TO PRODUCT-BASED LIBRARY DESIGN
Identify lists of potential reagents, filter them as needed, and enumerate the virtual library
Subject virtual library to virtual screening to evaluate and score each structure
Select reagents from results of virtual screening plus additional criteria (degree of structural diversity required, degree of similarity or dissimilarity to existing collections)
Usually done with optimization techniques (e.g., genetic algorithms or simulated annealing)

13. Alternatives to Product-Based Library Design
Molecule-based methods
Appropriate for targeted or focused libraries
Relatively fast, especially when combined with optimization based on 2D properties

14. MULTIOBJECTIVE LIBRARY DESIGN
Optimizes multiple properties simultaneously
Balances diversity and focus
Could search for drug-like properties
Multiobjective Genetic Algorithm (MOGA)

15. PRACTICAL EXAMPLES OF LIBRARY DESIGN
See examples in the text for
Structure-Based Library Design
Library Design in Lead Optimization

16. TRENDS
Design of smaller, more focused libraries with as much information about the therapeutic target as possible
May use docking methods if target structure is known
Use pharmacophoric methods, 2D or physicochemical properties if some actives are known
Focus on compounds with “drug-like” physicochemical properties

17. New Combichem Techniques
Current emphasis on arrays of fewer, well-characterized compounds
Movement toward complex natural-product-like compounds

18. Recent Advances Natural-product-like libraries
Dynamic combinatorial chemistry
Combinatorial optimization of catalysts
Multi-component reactions

19. New Approaches Use biologically relevant building blocks
Use branching networks of reactions
Produce libraries of natural-product-like compounds
Make all possible combinations of both core skeletal structures and peripheral groups

20. New Approaches Dynamic Combichem (DCC)
Used to ID molecules that bind with high affinity to macromolecular receptors OR
Synthetic receptors that bind tightly to small molecules
Uses equilibrium forces to amplify compounds that bind well to targets

21. New Approaches Combi Catalysis
To discover and optimize catalysts
Novel Methods for Combinatorial Synthesis
New linkages for solid-phase synthesis
New multi-component reactions

22. New Combichem Techniques
Make compounds in parallel
Test them in parallel
Obtain new properties rapidly
Discrete compounds are produced by parallel synthesis or by mixing synthesis with directed sorting

23. Benefits to the Pharmaceutical Industry
Provides a stimulus for robot-controlled and immobilization strategies that allow high-throughput and multiple parallel approaches to drug discovery

24. Benefits to Materials Science
Combinatorial approaches now being applied to solid-state and materials applications
Also to search for new catalysts

25. NIH Roadmap http://nihroadmap.nih.gov/
Roadmap for Medical Research in the 21st Century
Includes: Molecular Libraries and Imaging
NIH will assemble a huge combinatorial library as a source of new drug candidates
PubChem Database

26. CombiChem Web Sites CombiChem Lab http://www.combichemlab.com
Combinatorial Chemistry and High Throughput Screening (Wendy Warr)