Combinatorial Chemistry and Library Design

1. Combinatorial Chemistry and Library Design C371 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 • http://pubchem.ncbi.nlm.nih.gov/

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