Traditionally, new drugs are developed by either making small changes to existing drugs or by individually testing thousands of compounds. Both of these methods require many hours of laborious chemical synthesis. However, new techniques that capitalize on the advances of modern technology are being applied in the drug industry to develop new drugs which decrease the cost and time required to discover and develop new drugs. Nuclear magnetic resonance (NMR) and x-ray crystallography can be used to analyze compounds in order to create three-dimensional images for detailed, visual analysis of those compounds. Applying these 3-D structures to the drug design process involves using either structure-based drug design (SBDD) or ligand-based drug design (LBDD).

SAR by NMR

Structure-activity relationship (SAR) by (NMR) is one tool that is commonly used to design and develop new drugs. This is the process "in which small organic molecules that bind to proximal subsites of a protein are identified, optimized, and linked together to produce high-affinity ligands."^[2]

ABT-737

One example of drug discovery using SAR by NMR includes the development of .^[3] This compound has been shown to effectively inhibit the over-expression of which is a protein that is commonly observed to be over-expressed in many types of cancers. It acts an inhibitor of apoptosis and may also contribute to chemotherapy resistance. Bcl-xl inhibition by ABT-737 therefore, allows apoptosis to occur and helps to prevent chemo-resistance.

How SAR by NMR was used to develop ABT-737

Three ligands with moderate affinity for Bcl-xl were analyzed using SAR by NMR in order to develop ABT-737. The structural components that allow the ligands to bind to the protein were then linked together to form ABT-737 - the final compound with high-affinity for Bcl-xl.

is a 4'-fluoro-biphenyl-4-carboxylic acid. SAR by NMR was used to identify the interactions that this compound forms with Bcl-xl. The fluorobiphenyl system is hydrophobic and its interactions form a around the fluorobiphenyl system. The of Bcl-xl. The carboxylic acid is later substituted with an acyl sulfonamide (shown in compounds 2 & 3) which provides increased affinity.

binds with high affinity to Bcl-xl. However, this affinity was decreased in the presence of human serum albumin (HSA). In order to decrease HSA affinity, and therefore increase Bcl-xl affinity, SAR by NMR was used to modify compound 1 by eliminating key binding groups of compound 1 without affecting Bcl-xl affinity.

Once the components responsible for binding are identified, they can be modified, as in the case of compound 1 where the carboxylic acid was substituted with an acyl sulfonamide, and then they are linked together to create a compound with optimal binding affinity.