Fragment-Based Drug Discovery

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Revision as of 21:00, 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).

Ligand- and Structure-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] 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.

1 SAR by NMR
- 1.1 ABT-737
  - 1.1.1 Precursors to ABT-737

SAR by NMR

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."^[2] 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.

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.

ABT-737

One example of drug discovery using SAR by NMR includes the development of .^[3] This compound has been shown to effectively inhibit the over-expression of . 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.

Precursors to ABT-737

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.

is one of the precursors to ABT-737. It actually consists of two ligands: a and a . 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 and is also contained in the other two precursors. Because of of the ortho-hydrogens, the two benzene rings adopt a of about 28.6° as opposed to an angle of 0° (or perfectly lined up), therefore making the system very stable.

The other precursors, compound 2 and compound 3, are very similar in structure and contribute many of the same groups needed for high affinity. is an acylsulfonamide-based ligand while is a nitrobenzenesulfonamide-based ligand. Both of these compounds have the same core structure with the exception of the (shown with yellow halos) on the terminal benzene ring. These compounds also exhibit hydrophobic bonding with the fluorobiphenyl system but include a between an oxygen from the sulfoxone portion of the ligand to an "N-H" group of a glycine amino acid.

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
↑ 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.
↑ 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

Proteopedia Page Contributors and Editors (what is this?)

Justin Weekley, Arthur Cox, Jaime Prilusky

Retrieved from "http://52.214.119.220/wiki/index.php/Fragment-Based_Drug_Discovery"

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 = 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).
-<div class="NavFrame collapsed">
+{| class="wikitable collapsible collapsed"
-  <div class="NavHead">Ligand- and Structure-Based Drug Design</div>
+! scope="col" width="5000px" | Ligand- and Structure-Based Drug Design
-  <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.
+|-
-  </div>
+| 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.
-</div>
+|}

Fragment-Based Drug Discovery

From Proteopedia

Revision as of 21:00, 28 October 2012

Drug Design: SAR by NMR

Contents

SAR by NMR

ABT-737

Precursors to ABT-737

References

Proteopedia Page Contributors and Editors (what is this?)

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