Structure-based combinatorial library design: methodologies and applications

Rational design of small focused libraries that are biased toward specific therapeutic targets is currently at the forefront of combinatorial library design. Various structure-based design strategies can be implemented in focused library design when the 3D structure of the target is available through X-ray or NMR determination. This review discusses the major methods and programs specifically developed for the purpose of designing combinatorial libraries under the constraint of the binding site of a biological target, with emphasis on their advantages and disadvantages. Examples of the successful application of these methodologies are highlighted, demonstrating their performances within the practical drug discovery process.