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| ===== Precursors to ABT-737 ===== | | ===== Precursors to ABT-737 ===== |
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| Several ligands were discovered to have moderate affinity for Bcl-xl. Using SAR by NMR, each of these precursors were analyzed for structural components and functional groups that are critical for Bcl-xl affinity.
| | Three ligands served as precursors in ABT-737 development. Each ligand exhibits moderate affinity for Bcl-xl. Using SAR by NMR, the structural components that allow the ligands to bind to the protein were analyzed and linked together to form a final compound with high-affinity for Bcl-xl, ABT-737. |
| Using the example of ABT-737
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| <scene name='Sandbox_reserved_394/Compound_1/1'>Compound 1</scene> 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>. The fluorobiphenyl system is significant to the high affinity of ABT-737. 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 two subsequent compounds. Notice the stability of the biphenyl system. 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).
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| <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 1 is an acylsulfonamide-based ligand while compound 2 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 they also 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. | | <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. |
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| SAR by NMR is also useful for analyzing a drug target to obtain a better understanding of its function and activity as well as identifying similar targets. For example, Bcl-2 and Bcl-w are proteins that were discovered to have structures very closely related to Bcl-xl as well as similar roles as anti-apoptotic proteins.
| | 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. |
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| | </StructureSection> |
| === Bcl-xl: a member of the Bcl-2 family ===
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| ----
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| <scene name='Sandbox_reserved_394/Bcl-xl/1'>Bcl-xl</scene> is a member of the Bcl-2 family. The protein is comprised of seven <scene name='Sandbox_reserved_394/Alpha_helices/1'>alpha helices</scene>, no beta sheets, and 221 amino acid residues. | |
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| ==== Bcl-xl Inhibition with ABT-737 ====
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| Inhibiting the over-expression of this protein has been shown to effectively induce tumor regression and increase chemo-sensitivity. This can be done with<ref name="name" /><ref name="name">details of the citation</ref> . </StructureSection>
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| = References = | | = References = |
| <references/> | | <references/> |