Fragment-Based Drug Discovery

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= Discovering ABT-737: a Pro-apoptotic Agent =
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= Ligand-Based Drug Design =
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<StructureSection load='1ysi' size='500' side='right' caption=' ' scene='Sandbox_reserved_394/Bcl-xl/1'>
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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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In many forms of cancer, a family of proteins, known as the BCL-2 family, has been observed as being over-expressed. This over-expression prevents apoptosis from occurring and may also contribute resistance to chemotherapy.
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<StructureSection load='1ysi' size='500' side='right' caption=' ' scene='Sandbox_reserved_394/Bcl-xl/1'>
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=== ABT-737 ===
=== ABT-737 ===
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<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.
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<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.
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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.
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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 ====
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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>
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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 =
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{{Reflist}}
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[[User:Justin Weekley|Justin Weekley]] 03:20, 16 October 2012 (IST)
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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]

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. ↑ 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
  3. ↑ 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. ↑ 4.0 4.1 details of the citation

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