Fragment-Based Drug Discovery

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= Drug Design: SAR by NMR =
= Drug Design: SAR by NMR =
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Traditionally, new drugs are developed by either making small changes to existing drugs or by individually testing thousands of compounds. Both of these methods require many hours of laborious chemical synthesis. However, new techniques that capitalize on the advances of modern technology are being applied in the drug industry to develop new drugs which decrease the cost and time required to discover and develop new drugs. Nuclear magnetic resonance (NMR) and x-ray crystallography can be used to analyze compounds in order to create three-dimensional images for detailed, visual analysis. Using these 3-D structures to design drugs has been divided into two categories: ligand-based drug design (LBDD) and structure-based drug design (SBDD).
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Traditionally, new drugs are developed by either making small changes to existing drugs or by individually testing thousands of compounds. Both of these methods require many hours of laborious chemical synthesis. However, new techniques that capitalize on the advances of modern technology are being applied in the drug industry to develop new drugs which decrease the cost and time required to discover and develop new drugs. Nuclear magnetic resonance (NMR) and x-ray crystallography can be used to analyze compounds in order to create three-dimensional images for detailed, visual analysis of those compounds. Applying these 3-D structures to the drug design process involves using either structure-based drug design (SBDD) or ligand-based drug design (LBDD).
{| class="wikitable collapsible collapsed"
{| class="wikitable collapsible collapsed"
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! scope="col" width="5000px" | Ligand- and Structure-Based Drug Design
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! scope="col" width="5000px" | Structure-Based Drug Design
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| scope="col" width="5000px" | "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> In other words, once it is known how a ligand binds to a protein or any other molecule, new ligands, and eventually drugs, can be designed to bind in a similar manner and get the desired effect.
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| scope="col" width="5000px" | Structure-based drug design is utilized when the 3-D structure of a protein, or other drug target, is used to predict drug candidates. A visual representation of the structure allows developers to pinpoint binding sites and more effectively design a drug that will have high affinity for the target.
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{| class="wikitable collapsible collapsed"
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! scope="col" width="5000px" | Ligand-Based Drug Design
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|-
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| scope="col" width="5000px" | "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> In other words, once it is known how a ligand binds to a protein or any other molecule, new ligands, and eventually drugs, can be designed to bind in a similar manner and get the desired effect. It involves modifying a known ligand to develop another ligand with a higher binding affinity for the target.
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=== SAR by NMR ===
=== SAR by NMR ===
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One tool used in ligand-based design is structure-activity relationship (SAR) by (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> This process involves analyzing ligands that have some affinity for a protein or other molecule and identifying the structural components of the ligands that are responsible for the binding affinity.
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One tool used in the drug design process is structure-activity relationship (SAR) by (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>
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SAR by NMR has high potential for drug development as it can be used to develop drugs that have very high affinity for specific drug targets. Using this tool also 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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==== ABT-737 ====
==== ABT-737 ====
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One example of drug discovery using SAR by NMR includes the development of <scene name='Sandbox_reserved_394/Abt-737/1'>ABT-737</scene>.<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 been shown to effectively inhibit the over-expression of <scene name='Sandbox_reserved_394/Bcl-xl/1'>Bcl-xl</scene>. This protein is commonly observed to be over-expressed in many types of cancers and is an inhibitor of apoptosis and may also contribute to chemotherapy resistance. Bcl-xl inhibition by ABT-737 therefore, allows apoptosis to occur and helps to prevent chemo-resistance.
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One example of drug discovery using SAR by NMR includes the development of <scene name='Sandbox_reserved_394/Abt-737/1'>ABT-737</scene>.<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 been shown to effectively inhibit the over-expression of <scene name='Sandbox_reserved_394/Bcl-xl/1'>Bcl-xl</scene> which is a protein that is commonly observed to be over-expressed in many types of cancers. It acts an inhibitor of apoptosis and may also contribute to chemotherapy resistance. Bcl-xl inhibition by ABT-737 therefore, allows apoptosis to occur and helps to prevent chemo-resistance.
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===== How SAR by NMR was used to develop ABT-737 =====
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===== Precursors to ABT-737 =====
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Three ligands with moderate affinity for Bcl-xl were analyzed using SAR by NMR in order to develop ABT-737. The structural components that allow the ligands to bind to the protein were then linked together to form ABT-737 - the final compound with high-affinity for Bcl-xl.
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Three ligands served as precursors in ABT-737 development. Each ligand exhibits moderate affinity for Bcl-xl. Using SAR by NMR, the structural components that allow the ligands to bind to the protein were analyzed and linked together to form a final compound with high-affinity for Bcl-xl, ABT-737.
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<scene name='Sandbox_reserved_394/Compound_1/2'>Compound 1</scene> is a fluorobiphenyl derivative. SAR by NMR was used to identify the hydrophobic interactions that this compound forms with Bcl-xl. These interactions form a <scene name='Sandbox_reserved_394/Compound_1/4'>"hydrophobic pocket"</scene> around the fluorobiphenyl system.
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<scene name='Sandbox_reserved_394/Compound_1/1'>Compound 1</scene> is one of the precursors to ABT-737. It actually consists of two ligands: a <scene name='Sandbox_reserved_394/Compound_1/2'>fluorobiphenyl-based ligand</scene> and a <scene name='Sandbox_reserved_394/Compound_1/3'>naphthalene derivative</scene>. Using SAR by NMR, the fluorobiphenyl system was discovered to be significant to the affinity of the ligand. It is involved in hydrophobic interactions with Bcl-xl forming a <scene name='Sandbox_reserved_394/Compound_1/4'>"hydrophobic pocket"</scene> and is also contained in the other two precursors. Because of <scene name='Sandbox_reserved_394/Compound_1_steric_hindrance/1'>steric hindrance</scene> of the ortho-hydrogens, the two benzene rings adopt a <scene name='Sandbox_reserved_394/Compound_1_dihedral_angle/1'>dihedral angle</scene> of about 28.6° as opposed to an angle of 0° (or perfectly lined up), therefore making the system very stable.
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<scene name='Sandbox_reserved_394/Compound_1/3'>Compound 2</scene> is a 4-biphenylcarboxylic acid.
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The other precursors, compound 2 and compound 3, are very similar in structure and contribute many of the same groups needed for high affinity. <scene name='Sandbox_reserved_394/Compound_2/1'>compound 2</scene> is an acylsulfonamide-based ligand while <scene name='Sandbox_reserved_394/Compound_3/1'>compound 3</scene> 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 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.
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Compound 3 and compound 4, are very similar in structure and contribute many of the same groups needed for high affinity. <scene name='Sandbox_reserved_394/Compound_2/1'>compound 4</scene> is an acylsulfonamide-based ligand while <scene name='Sandbox_reserved_394/Compound_3/1'>compound 3</scene> 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 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.
</StructureSection>
</StructureSection>

Revision as of 15:00, 29 October 2012

Drug Design: SAR by NMR

Traditionally, new drugs are developed by either making small changes to existing drugs or by individually testing thousands of compounds. Both of these methods require many hours of laborious chemical synthesis. However, new techniques that capitalize on the advances of modern technology are being applied in the drug industry to develop new drugs which decrease the cost and time required to discover and develop new drugs. Nuclear magnetic resonance (NMR) and x-ray crystallography can be used to analyze compounds in order to create three-dimensional images for detailed, visual analysis of those compounds. Applying these 3-D structures to the drug design process involves using either structure-based drug design (SBDD) or ligand-based drug design (LBDD).


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. ↑ 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.
  3. ↑ 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

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