Fragment-Based Drug Discovery: Difference between revisions
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===== ABT-737: ligand optimization ===== | ===== ABT-737: ligand optimization ===== | ||
Compounds 1 & 2 exhibited very poor binding affinity for Bcl-xl. The optimization of these two compounds resulted in <scene name='Sandbox_reserved_394/Compound_2/1'>Compound | Compounds 1 & 2 exhibited very poor binding affinity for Bcl-xl. The optimization of these two compounds resulted in <scene name='Sandbox_reserved_394/Compound_2/1'>Compound 3</scene>. In order to improve the binding affinity, the carboxylic acid of compound 1 was substituted with an acyl sulfonamide to capitalize on the hydrophilic interaction with the protein. This <scene name='Sandbox_reserved_394/Compound_2/2'>acylsulfonamide portion forms a hydrogen bond with Gly 142</scene> thereby increasing the affinity for Bcl-xl. The substitution of the sulfonamide actually allows the acidic proton to get closer to Gly 142 than it could in the carboxylic acid, which is why it is able to bind stronger to the amino acid. | ||
Compound 2 was important in identifying the hydrophobicity of binding site 2 but was substituted with a <scene name='Sandbox_reserved_394/Nitro_thio_phenyl_sub/1'>3-nitro-4-(2-phenylthioethyl)aminophenyl group</scene>. This substitution "spans the binding sites and efficiently occupies site 2 through hydrophobic collapse and subsequent p–p stacking." | Compound 2 was important in identifying the hydrophobicity of binding site 2 but was substituted with a <scene name='Sandbox_reserved_394/Nitro_thio_phenyl_sub/1'>3-nitro-4-(2-phenylthioethyl)aminophenyl group</scene>. This substitution "spans the binding sites and efficiently occupies site 2 through hydrophobic collapse and subsequent p–p stacking." | ||
