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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.

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combinatorial chemistry and library design

Combinatorial Chemistry and Library Design


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
  • 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
  • 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
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
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
  • 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 approaches20
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 approaches21
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 techniques22
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
  • 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
combichem web sites
CombiChem Web Sites
  • CombiChem Lab
  • Combinatorial Chemistry and High Throughput Screening (Wendy Warr)