Fragment-Based Drug Discovery: Difference between revisions

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Arthur Cox, Justin Weekley, Jaime Prilusky

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 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.
-<scene name='Sandbox_reserved_394/Compound_1/2'>Compound 1</scene> 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 <scene name='Sandbox_reserved_394/Compound_1/4'>"hydrophobic pocket"</scene> around the fluorobiphenyl system.
+<scene name='Sandbox_reserved_394/Compound_1/2'>Compound 1</scene> is 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 <scene name='Sandbox_reserved_394/Compound_1/4'>"hydrophobic pocket"</scene> around the fluorobiphenyl system. The <scene name='Sandbox_reserved_394/Compound_1/5'>carboxyilic acid portion binds near Gly 142</scene> of Bcl-xl. The carboxylic acid is later substituted with an acyl sulfonamide (shown in compounds 2 & 3) which provides increased affinity.
-<scene name='Sandbox_reserved_394/Compound_1/3'>Compound 2</scene> is a 4-biphenylcarboxylic acid.
+<scene name='Sandbox_reserved_394/Compound_2/1'>Compound 2</scene> 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.
-Compound 3 and compound 4, are very similar in structure and contribute many of the same groups needed for high affinity. <scene name='Sandbox_reserved_394/Compound_2/1'>compound 4</scene> is an acylsulfonamide-based ligand while <scene name='Sandbox_reserved_394/Compound_3/1'>compound 3</scene> is a nitrobenzenesulfonamide-based ligand. Both of these compounds have the same core structure with the exception of the <scene name='Sandbox_reserved_394/Compound_3_methyls/3'>two methyl substituents</scene> (shown with yellow halos) on the terminal benzene ring. These compounds also exhibit hydrophobic bonding with the fluorobiphenyl system but include a <scene name='Sandbox_reserved_394/Hydrogen_bonds/7'>hydrogen bond</scene> between an oxygen from the sulfoxone portion of the ligand to an "N-H" group of a glycine amino acid.
+{| class="wikitable collapsible collapsed"
+! scope="col" width="5000px" | Modifying compound 1 to reduce HSA affinity
+|-
+| scope="col" width="5000px" | this figure
+|}
+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.
 </StructureSection>