Fragment-Based Drug Discovery

Ligand-Based Drug Design: SAR by NMR

"Ligand-based drug design (LBDD) techniques are applied when the structure of the receptor is unknown but when a series of compounds or ligands have been identified that show the biological activity of the interest." In other words, once it is known how a ligand binds to a protein or any other molecule, new ligands, and eventually drugs, can be designed to bind in a similar manner and get the desired effect.

spinqualitylabelsall models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D 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." This process involves 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 ABT-737. This compound has been shown to effectively inhibit the over-expression of Bcl-xl. 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 Three ligands served as precursors in ABT-737 development. Each ligand exhibits moderate affinity for Bcl-xl. Using SAR by NMR, the structural components that allow the ligands to bind to the protein were analyzed and linked together to form a final compound with high-affinity for Bcl-xl, ABT-737. Compound 1 is one of the precursors to ABT-737. It actually consists of two ligands: a fluorobiphenyl-based ligand and a naphthalene derivative. Using SAR by NMR, the fluorobiphenyl system was discovered to be significant to the affinity of the ligand. It is involved in hydrophobic interactions with Bcl-xl forming a "hydrophobic pocket" and is also contained in the other two precursors. Because of steric hindrance of the ortho-hydrogens, the two benzene rings adopt a dihedral angle of about 28.6° as opposed to an angle of 0° (or perfectly lined up), therefore making the system very stable. The other precursors, compound 2 and compound 3, are very similar in structure and contribute many of the same groups needed for high affinity. compound 2 is an acylsulfonamide-based ligand while compound 3 is a nitrobenzenesulfonamide-based ligand. Both of these compounds have the same core structure with the exception of the two methyl substituents (shown with yellow halos) on the terminal benzene ring. These compounds also exhibit hydrophobic bonding with the fluorobiphenyl system but include a hydrogen bond between an oxygen from the sulfoxone portion of the ligand to an "N-H" group of a glycine amino acid.

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Justin Weekley, Arthur Cox, Jaime Prilusky