Combinatorial Chemistry and Library Design.pptVIP

Combinatorial Chemistry and Library Design C371 Chemical Informatics Lecture Based largely on the CEN 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