Fragment-Based Drug Discovery

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Bcl-xl is a protein that is over-expressed in many forms of cancers and is an initiator of tumor formation.<ref>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</ref> There is also evidence that Bcl-xl expression may also contribute to chemo-resistance. Paclitaxel, a member of the <scene name='Sandbox_reserved_394/Abt-737/1'>ABT-737</scene> family, has been show to effectively inhibit the over-expression of this protein thereby inducing tumor regression and increasing chemo-sensitivity.
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Bcl-xl is a protein that is over-expressed in many forms of cancers and is an initiator of tumor formation.<ref>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</ref> There is also evidence that Bcl-xl expression may also contribute to chemo-resistance.
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Shown here is the interaction between paclitaxel and the protein via <scene name='Sandbox_reserved_394/Hydrogen_bonds/7'>hydrogen bond</scene>. The hydrogen bond is formed between an oxygen from the sulfoxone portion of the drug to an "N-H" group of a glycine amino acid. This forms one of the intermolecular or "weak" bonds between the drug and protein.
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The ligand is a member of the <scene name='Sandbox_reserved_394/Abt-737/1'>ABT-737</scene> family. ABT-737 has been shown to effectively inhibit the over-expression of this protein thereby inducing tumor regression and increasing chemo-sensitivity.
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Shown here is a sort of <scene name='Sandbox_reserved_394/Hydrophobic_bonding/7'>"pocket"</scene> formed between the protein (red) and hydrophobic, or "water hating", portions of paclitaxel. This is an example of hydrophobic bonding formed by intermolecular forces between some hydrophobic sections of the protein with hydrophobic portions of the ligand.
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Shown here is the interaction between the ligand and the protein via <scene name='Sandbox_reserved_394/Hydrogen_bonds/7'>hydrogen bond</scene>. The hydrogen bond is formed between an oxygen from the sulfoxone portion of the drug to an "N-H" group of a glycine amino acid. This forms one of the intermolecular or "weak" bonds between the drug and protein.
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Shown here is a sort of <scene name='Sandbox_reserved_394/Hydrophobic_bonding/7'>"pocket"</scene> formed between the protein (red) and hydrophobic, or "water hating", portions of the acyl-sulfonamide. This is an example of hydrophobic bonding formed by intermolecular forces between some hydrophobic sections of the protein with hydrophobic portions of the ligand.

Revision as of 00:17, 3 October 2012

Anti-Apoptotic Protein: Bcl-xl

Structure of Bcl-xl/Paclitaxel complex (PDB entry 1ysi)

Drag the structure with the mouse to rotate

References

  1. ↑ 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

Proteopedia Page Contributors and Editors (what is this?)

Justin Weekley, Arthur Cox, Jaime Prilusky

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