| Combinatorial Chemistry and Library Design : 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 : 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 : Combichem Techniques Tools
Solid-phase synthesis
Resins
Reagents (Monomers)
Linkers
Screening methods |
| Combichem 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 : 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 : Problems with Early Combichem Libraries Many compounds had undesirable properties:
Size
Solubility
Inappropriate functional groups |
| Criticism of the Technique : 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 : 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 : 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) : 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 : 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
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| APPROACHES TO PRODUCT-BASED LIBRARY DESIGN : 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 : 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 : MULTIOBJECTIVE LIBRARY DESIGN Optimizes multiple properties simultaneously
Balances diversity and focus
Could search for drug-like properties
Multiobjective Genetic Algorithm (MOGA)
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| PRACTICAL EXAMPLES OF LIBRARY DESIGN : PRACTICAL EXAMPLES OF LIBRARY DESIGN See examples in the text for
Structure-Based Library Design
Library Design in Lead Optimization |
| TRENDS : 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 : New Combichem Techniques Current emphasis on arrays of fewer, well-characterized compounds
Movement toward complex natural-product-like compounds |
| Recent Advances : Recent Advances Natural-product-like libraries
Dynamic combinatorial chemistry
Combinatorial optimization of catalysts
Multi-component reactions |
| New Approaches : 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 : 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
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| New Approaches : 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 : 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 : 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 : Benefits to Materials Science Combinatorial approaches now being applied to solid-state and materials applications
Also to search for new catalysts |
| NIH Roadmap : 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/
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| CombiChem Web Sites : CombiChem Web Sites CombiChem Lab http://www.combichemlab.com
Combinatorial Chemistry and High Throughput Screening (Wendy Warr) http://www.warr.com/ombichem.html
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