Fragment-Based Drug Discovery
From Proteopedia
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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 may occur in damaged cells and 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.<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 to suggest that Bcl-2 over-expression may also contribute to chemo-resistance. | 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 may occur in damaged cells and 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.<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 to suggest that Bcl-2 over-expression may also contribute to chemo-resistance. | ||
| - | + | <StructureSection load='1ysi' size='500' side='right' caption=' ' scene='Sandbox_reserved_394/Bcl-xl/1'> | |
__TOC__ | __TOC__ | ||
| - | <Structure load='1ysi' size='500' frame='true' align='right' caption=' ' scene='Sandbox_reserved_394/Bcl-xl/1' /> | ||
=== Bcl-xl: a member of the Bcl-2 family === | === Bcl-xl: a member of the Bcl-2 family === | ||
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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_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. | ||
| - | 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. | + | 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.</StructureSection> |
= References = | = References = | ||
Revision as of 18:57, 17 October 2012
Apoptosis by Inhibition of Bcl-2 Family Proteins
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 may occur in damaged cells and 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.
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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
- ↑ 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.
Justin Weekley 03:20, 16 October 2012 (IST)
