SAR by NMR

One tool used in ligand-based design is structure-activity relationship (SAR) by nuclear magnetic resonance (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] This is the process of analyzing ligands that have some affinity for a protein or other molecule and identifying the structural components of the ligands that are responsible for the binding affinity.

SAR by NMR has high potential for drug development as it can be used to develop drugs that have very high affinity for specific drug targets. Using this tool also allows drug developers to create new drugs with minimal chemical synthesis, which then decreases the cost and time required to discover and develop new drugs.

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 . This protein is commonly observed to be over-expressed in many types of cancers and is 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.

Precursors to ABT-737

Several ligands were discovered to have moderate affinity for Bcl-xl. Using SAR by NMR, each of these precursors were analyzed for structural components and functional groups that are critical for Bcl-xl affinity. Using the example of ABT-737 actually consists of two ligands: a and a . The fluorobiphenyl system is significant to the high affinity of ABT-737. It is involved in hydrophobic interactions with Bcl-xl forming a and is also contained in the two subsequent compounds. Notice the stability of the biphenyl system. Because of of the ortho-hydrogens, the two benzene rings adopt a of about 28.6° as opposed to an angle of 0° (or perfectly lined up).

and are very similar in structure and contribute many of the same groups needed for high affinity. Coumpound 1 is an acylsulfonamide-based ligand while compound 2 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 they also include a between an oxygen from the sulfoxone portion of the ligand to an "N-H" group of a glycine amino acid.

SAR by NMR is also useful for analyzing a drug target to obtain a better understanding of its function and activity as well as identifying similar targets. For example, Bcl-2 and Bcl-w are proteins that were discovered to have structures very closely related to Bcl-xl as well as similar roles as anti-apoptotic proteins.

Bcl-xl: a member of the Bcl-2 family

is a member of the Bcl-2 family. The protein is comprised of seven , no beta sheets, and 221 amino acid residues.

Bcl-xl Inhibition with ABT-737

Inhibiting the over-expression of this protein has been shown to effectively induce tumor regression and increase chemo-sensitivity. This can be done with^[4][4] .