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A paradigm for drug discovery employing encoded combinatorial libraries
J J Burbaum1, M H Ohlmeyer, J C Reader
1Department of Biology, Pharmacopeia, Inc., Princeton, NJ 08540, USA.
Summary
Tag-encoded chemical libraries enable efficient drug discovery. Researchers synthesized and tested large molecule libraries targeting carbonic anhydrase, identifying potent inhibitors with nanomolar activity.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Drug Discovery
Background:
- Combinatorial libraries on solid supports can be synthesized and identified using chemical tags.
- Tag-encoded libraries offer a promising avenue for drug discovery.
- Carbonic anhydrase (EC 4.2.1.1) was selected as a model target to evaluate this approach.
Purpose of the Study:
- To assess the utility of tag-encoded combinatorial libraries in drug discovery.
- To identify novel inhibitors of carbonic anhydrase.
- To establish structure-activity relationships for carbonic anhydrase inhibitors.
Main Methods:
- Synthesis of two large tag-encoded combinatorial libraries (7870 members total).
- Derivation of structure-activity relationships based on tag-predicted structures.
- Resynthesis of active library representatives and characterization of their binding affinity.
- Synthesis of a focused sulfamoylbenzamide sublibrary.
Main Results:
- Identified potent carbonic anhydrase inhibitors with nanomolar dissociation constants (15 nM and 4 nM).
- Established clear structure-activity relationships for isozyme-selective inhibitors within the sulfamoylbenzamide class.
- Demonstrated the effectiveness of tag-encoded libraries for lead identification.
Conclusions:
- Tag-encoded combinatorial libraries are a powerful tool for accelerating drug discovery.
- The study identified novel, potent inhibitors of carbonic anhydrase.
- Structure-activity relationship analysis enabled the design of isozyme-selective inhibitors.