Fragment-Based Drug Discovery

From Proteopedia

(Difference between revisions)

@@ Line 15: / Line 15: @@
 ==== Bcl-xl Inhibition ====
-Inhibition of the over-expression of this protein has been shown to be effective at inducing tumor regression and increasing chemo-sensitivity. This represents the binding of an <scene name='Sandbox_reserved_394/Paclitaxel/1'>acyl-sulfonamide</scene> to the anti-apoptotic protein, .
+Inhibiting the over-expression of this protein has been shown to effectively at induce tumor regression and increase chemo-sensitivity. This can be done with an <scene name='Sandbox_reserved_394/Paclitaxel/1'>acylsulfonamide-based ligand</scene>.
+==== Intermolecular Binding ====
-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.
-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.
+There are several intermolecular, or "weak", bonds at work to form the complex. This type of bonding is responsible for
+There is one <scene name='Sandbox_reserved_394/Hydrogen_bonds/7'>hydrogen bond</scene> at work in this complex. The 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.
 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.
 Click on each amino acid to view the hydrophobic interactions with the ligand:
@@ Line 38: / Line 36: @@
 | align="center" | <scene name='Sandbox_reserved_394/Phe109_and_ala108/1'>Ala108</scene> || align="center" | <scene name='Sandbox_reserved_394/Tyrosine_105/1'>Tyr105</scene> || align="center" | <scene name='Sandbox_reserved_394/Phe_101/1'>Phe101</scene> || align="center" | <scene name='Sandbox_reserved_394/Glycine_142/1'>Gly142</scene>
 |}
+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.

Revision as of 01:46, 3 October 2012

Apoptosis by Inhibition of Bcl-2 Family Proteins

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

Show:Asymmetric Unit Biological Assembly

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Apoptosis, or programmed cell death, is a natural mechanism in which a damaged cell dies in order to prevent further damage to the multicellular organism. The absence of apoptosis in damaged cells can lead to many types of cancers and other diseases. In certain types of cancers, a family of proteins, known as the Bcl-2 family, has been observed as being over-expressed compared to normal, healthy cells.^[1] There is also evidence to suggest that Bcl-2 over-expression may also contribute to chemo-resistance.

1 Bcl-xl: a member of the Bcl-2 family
- 1.1 Bcl-xl Inhibition
- 1.2 Intermolecular Binding

Bcl-xl: a member of the Bcl-2 family

is a member of the Bcl-2 family. The protein is comprised of seven , no beta sheets, and 221 amino acid residues.

Bcl-xl Inhibition

Inhibiting the over-expression of this protein has been shown to effectively at induce tumor regression and increase chemo-sensitivity. This can be done with an .

Intermolecular Binding

There are several intermolecular, or "weak", bonds at work to form the complex. This type of bonding is responsible for There is one at work in this complex. The 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.

Shown here is a sort of 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.

Click on each amino acid to view the hydrophobic interactions with the ligand:

The ligand is a member of the family. ABT-737 has been shown to effectively inhibit the over-expression of this protein thereby inducing tumor regression and increasing chemo-sensitivity.

References

↑ 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