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
Use of more diverse libraries when little is known about the target
Primary screening libraries Give broad coverage of chemistry space
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
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
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
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
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/