Combinatorial Chemistry and
Library Design
C371
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
