SAR by NMR
One tool used in the drug design process is structure-activity relationship (SAR) by (NMR). This is a 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 fluorobiphenyl derivative. SAR by NMR was used to identify the hydrophobic interactions that this compound forms with Bcl-xl. These interactions form a around the fluorobiphenyl system.
is a 4-biphenylcarboxylic acid.
Compound 3 and compound 4, are very similar in structure and contribute many of the same groups needed for high affinity. is an acylsulfonamide-based ligand while is a nitrobenzenesulfonamide-based ligand. Both of these compounds have the same core structure with the exception of the (shown with yellow halos) on the terminal benzene ring. These compounds also exhibit hydrophobic bonding with the fluorobiphenyl system but include a between an oxygen from the sulfoxone portion of the ligand to an "N-H" group of a glycine amino acid.
