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 and create three-dimensional images for further analysis. "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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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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<div class="NavHead">Ligand- and Structure-Based Drug Design</div>
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<div class="NavContent">"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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<StructureSection load='1ysi' size='500' side='right' caption=' ' scene='Sandbox_reserved_394/Bcl-xl/1'>
<StructureSection load='1ysi' size='500' side='right' caption=' ' scene='Sandbox_reserved_394/Bcl-xl/1'>
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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.
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.
</StructureSection>
</StructureSection>
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= References =
= References =
<references/>
<references/>

Revision as of 20:31, 28 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. 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).


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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