Fragment-Based Drug Discovery: Difference between revisions

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<scene name='Sandbox_reserved_394/Compound_1/1'>Compound 1</scene> is one of the precursors to ABT-737. It actually consists of two ligands: a <scene name='Sandbox_reserved_394/Compound_1/2'>fluorobiphenyl-based ligand</scene> and a <scene name='Sandbox_reserved_394/Compound_1/3'>naphthalene derivative</scene>. 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 <scene name='Sandbox_reserved_394/Compound_1/4'>"hydrophobic pocket"</scene> and is also contained in the other two precursors. Because of <scene name='Sandbox_reserved_394/Compound_1_steric_hindrance/1'>steric hindrance</scene> of the ortho-hydrogens, the two benzene rings adopt a <scene name='Sandbox_reserved_394/Compound_1_dihedral_angle/1'>dihedral angle</scene> of about 28.6° as opposed to an angle of 0° (or perfectly lined up), therefore making the system very stable.
<scene name='Sandbox_reserved_394/Compound_1/1'>Compound 1</scene> is one of the precursors to ABT-737. It actually consists of two ligands: a <scene name='Sandbox_reserved_394/Compound_1/2'>fluorobiphenyl-based ligand</scene> and a <scene name='Sandbox_reserved_394/Compound_1/3'>naphthalene derivative</scene>. 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 <scene name='Sandbox_reserved_394/Compound_1/4'>"hydrophobic pocket"</scene> and is also contained in the other two precursors. Because of <scene name='Sandbox_reserved_394/Compound_1_steric_hindrance/1'>steric hindrance</scene> of the ortho-hydrogens, the two benzene rings adopt a <scene name='Sandbox_reserved_394/Compound_1_dihedral_angle/1'>dihedral angle</scene> of about 28.6° as opposed to an angle of 0° (or perfectly lined up), therefore making the system very stable.


The other precursors, <scene name='Sandbox_reserved_394/Compound_2/1'>compound 2</scene> and <scene name='Sandbox_reserved_394/Compound_3/1'>compound 3</scene>, are very similar in structure and contribute many of the same groups needed for high affinity. Coumpound 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 <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.
The other precursors, compound 2 and compound 3, 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 2</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.
</StructureSection>
</StructureSection>


= References =
= References =
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