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

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

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

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

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

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

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

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

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

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/

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