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Fragment-Based Drug Discovery
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| - | = | + | = Ligand-Based Drug Design = |
| - | < | + | 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.<ref name="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">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</ref> |
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| + | <StructureSection load='1ysi' size='500' side='right' caption=' ' scene='Sandbox_reserved_394/Bcl-xl/1'> | ||
__TOC__ | __TOC__ | ||
=== ABT-737 === | === ABT-737 === | ||
---- | ---- | ||
| - | <scene name='Sandbox_reserved_394/Abt-737/1'>ABT-737</scene> has been shown to effectively inhibit the over-expression of the Bcl-2 family of proteins, and thus allowing apoptosis to occur and preventing chemo-resistance. This compound has very high affinity for <scene name='Sandbox_reserved_394/Bcl-xl/1'>Bcl-xl</scene>, which is a specific protein of the Bcl-2 family. | + | <scene name='Sandbox_reserved_394/Abt-737/1'>ABT-737</scene> has been shown to effectively inhibit the over-expression of the Bcl-2 family of proteins, and thus allowing apoptosis to occur and preventing chemo-resistance.<ref name="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">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> This compound has very high affinity for <scene name='Sandbox_reserved_394/Bcl-xl/1'>Bcl-xl</scene>, which is a specific protein of the Bcl-2 family. |
=== SAR by NMR === | === SAR by NMR === | ||
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Once it is known how a ligand binds to a protein or any other molecule, new ligands can be designed to bind in a similar manner and get the desired effect. This process is known as ligand-based design. The use of this method has resulted in the discovery and production of many medicinal agents available for phramacologic therapy, including ABT-737. | Once it is known how a ligand binds to a protein or any other molecule, new ligands can be designed to bind in a similar manner and get the desired effect. This process is known as ligand-based design. The use of this method has resulted in the discovery and production of many medicinal agents available for phramacologic therapy, including ABT-737. | ||
| - | One tool used in ligand-based design is structure-activity relationship (SAR) by nuclear magnetic resonance (NMR). This is a process "in which small organic molecules that bind to proximal subsites of a protein are identified, optimized, and linked together to produce high-affinity ligands."<ref>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.</ref> Using this tool allows drug developers to create new drugs with minimal chemical synthesis, which then decreases the cost and time required to discover and develop new drugs. | + | One tool used in ligand-based design is structure-activity relationship (SAR) by nuclear magnetic resonance (NMR). This is a process "in which small organic molecules that bind to proximal subsites of a protein are identified, optimized, and linked together to produce high-affinity ligands."<ref name="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.">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.</ref> Using this tool allows drug developers to create new drugs with minimal chemical synthesis, which then decreases the cost and time required to discover and develop new drugs. |
Discovering ABT-737 involved a process of analyzing a series of precursors to the final ligand. Several compounds were found to have affinity for Bcl-xl. Using SAR by NMR, each of these precursors were analyzed for functional groups that were critical for high affinity binding. | Discovering ABT-737 involved a process of analyzing a series of precursors to the final ligand. Several compounds were found to have affinity for Bcl-xl. Using SAR by NMR, each of these precursors were analyzed for functional groups that were critical for high affinity binding. | ||
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==== Bcl-xl Inhibition with ABT-737 ==== | ==== Bcl-xl Inhibition with ABT-737 ==== | ||
| - | Inhibiting the over-expression of this protein has been shown to effectively induce tumor regression and increase chemo-sensitivity. This can be done with . </StructureSection> | + | 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> |
= References = | = References = | ||
| - | + | <references/> | |
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Revision as of 15:13, 23 October 2012
Ligand-Based Drug Design
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]
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References
- ↑ 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
- ↑ 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.
- ↑ 4.0 4.1 details of the citation
