Fragment-Based Drug Discovery

Drug Design: SAR by NMRDrug Design: SAR by NMR

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).

Structure-Based Drug Design
Structure-based drug design is utilized when the 3-D structure of a protein, or other drug target, is used to predict drug candidates. A visual representation of the structure allows developers to pinpoint binding sites and more effectively design a drug that will have high affinity for the target.

Ligand-Based Drug Design

"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. It involves modifying a known ligand to develop another ligand with a higher binding affinity for the target.

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." ABT-737 One example of drug discovery using SAR by NMR includes the development of . 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.

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