Fragment-Based Drug Discovery: Difference between revisions
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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. | 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 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 | <scene name='Sandbox_reserved_394/Compound_1/2'>Compound 1</scene> is a 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 compound 2) which provides increased affinity. | ||
<scene name='Sandbox_reserved_394/Compound_2/1'>Compound 2</scene> binds with high affinity to Bcl-xl. | <scene name='Sandbox_reserved_394/Compound_2/1'>Compound 2</scene> binds with high affinity to Bcl-xl. The <scene name='Sandbox_reserved_394/Compound_2/2'>acylsulfonamide portion forms a hydrogen bond with Gly 142</scene>. The substitution of this sulfonamide for the carboxylic acid from compound 1 allows compound 2 to form a much stronger bond with Bcl-xl by bringing the shared acidic proton in closer proximity to GLY 142. The binding affinity of compound 2 for Bcl-xl is greatly reduced 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 to HSA without affecting Bcl-xl affinity. | ||
{| class="wikitable collapsible collapsed" | {| class="wikitable collapsible collapsed" | ||
! scope="col" width="5000px" | Modifying compound | ! scope="col" width="5000px" | Modifying compound 2 to reduce HSA affinity | ||
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| scope="col" width="5000px" | this | | scope="col" width="5000px" | Compound 2 has high affinity for Bcl-xl but has an even higher affinity for HSA. For this reason, when HSA is present, compound 2 and similar ligands are more likely to bind to HSA thereby decreasing the amount that can bind with Bcl-xl. In order to decrease the affinity for HSA while maintaining affinity for Bcl-xl, SAR by NMR was used to compare compound 2 with a <scene name='Sandbox_reserved_394/Compound_3/1'>thioethylamino-2,4-dimethylphenyl analogue</scene>, which also has high affinity for HSA. It was found that two hydrophobic portions of compound 2 had very strong hydrophobic interactions with HSA. Therefore, these portions were modified with polar substituents to decrease HSA affinity. To decrease hydrophobicity, the fluorobiphenyl system was substituted with a piperazine ring and a 2-dimethylaminoethyl group was added to the thioethylamino linkage group. | ||
|} | |} | ||
