Combinatorial Chemistry and Library Design

C371Chemical 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