Fragment-Based Drug Discovery

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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.
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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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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 =
<references/>
<references/>

Revision as of 20:26, 24 October 2012

Ligand-Based Drug Design: SAR by NMR

"Ligand-based drug design (LBDD) techniques are applied when the structure of the receptor is unknown but when a series of compounds or ligands have been identified that show the biological activity of the interest."[1] In other words, once it is known how a ligand binds to a protein or any other molecule, new ligands, and eventually drugs, can be designed to bind in a similar manner and get the desired effect.

PDB ID 1ysi

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References

  1. ↑ Pandit D. LIGAND-BASED DRUG DESIGN: I. CONFORMATIONAL STUDIES OF GBR 12909 ANALOGS AS COCAINE ANTAGONISTS; II. 3D-QSAR STUDIES OF SALVINORIN A ANALOGS AS εΑΡΡΑ OPIOID AGONISTS. http://archives.njit.edu/vol01/etd/2000s/2007/njit-etd2007-051/njit-etd2007-051.pdf
  2. ↑ Shuker S. B., Hajduk P. J., Meadows R. P., Fesik S. W. Discovering High-Affinity Ligands for Proteins: SAR by NMR. Science; Nov 29, 1996; 274, 5292; ProQuest Central pg. 1531.
  3. ↑ Oltersdorf T., Elmore S. W., Shoemaker A. R. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Vol 435|2 June 2005|doi:10.1038/nature03579

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