Fragment-Based Drug Discovery

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Revision as of 04:19, 30 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).

Structure-Based Drug Design
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.

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] 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.

1 SAR by NMR
- 1.1 ABT-737
  - 1.1.1 How SAR by NMR was used to develop ABT-737

SAR by NMR

Structure-activity relationship (SAR) by (NMR) is one tool that is commonly used to design and develop new drugs. This is the 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]

SAR by NMR

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 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.

How SAR by NMR was used to develop ABT-737

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.

is a 4'-fluoro-biphenyl-4-carboxylic acid. SAR by NMR was used to identify the interactions that this compound forms with Bcl-xl. The fluorobiphenyl system is hydrophobic and its interactions form a around the fluorobiphenyl system. The of Bcl-xl. The carboxylic acid is later substituted with an acyl sulfonamide (shown in compound 2) which provides increased affinity.

binds with high affinity to Bcl-xl. The . The substitution of this sulfonamide for the carboxylic acid from compound 1 allows compound 2 to form a much stronger bond with Bcl-xl by bringing the shared acidic proton in closer proximity to GLY 142. The binding affinity of compound 2 for Bcl-xl is greatly reduced in the presence of human serum albumin (HSA). In order to decrease HSA affinity, and therefore increase Bcl-xl affinity, SAR by NMR was used to modify compound 1 by eliminating key binding groups of compound 1 to HSA without affecting Bcl-xl affinity.

Modifying compound 2 to reduce HSA affinity
Compound 2 has high affinity for Bcl-xl but has an even higher affinity for HSA. For this reason, when HSA is present, compound 2 and similar ligands are more likely to bind to HSA thereby decreasing the amount that can bind with Bcl-xl. In order to decrease the affinity for HSA while maintaining affinity for Bcl-xl, SAR by NMR was used to compare compound 2 with a , which also has high affinity for HSA. It was found that two hydrophobic portions of compound 2 had very strong hydrophobic interactions with HSA. Therefore, these portions were modified with polar substituents to decrease HSA affinity. To decrease hydrophobicity, the fluorobiphenyl system was substituted with a piperazine ring and a 2-dimethylaminoethyl group was added to the thioethylamino linkage group.

Once the components responsible for binding are identified, they can be modified, as in the case of compound 1 where the carboxylic acid was substituted with an acyl sulfonamide, and then they are linked together to create a compound with optimal binding affinity.

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"

@@ Line 27: / Line 27: @@
 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.
-<scene name='Sandbox_reserved_394/Compound_1/2'>Compound 1</scene> is a 4'-fluoro-biphenyl-4-carboxylic acid. SAR by NMR was used to identify the interactions that this compound forms with Bcl-xl. The fluorobiphenyl system is hydrophobic and its interactions form a <scene name='Sandbox_reserved_394/Compound_1/4'>"hydrophobic pocket"</scene> around the fluorobiphenyl system. The <scene name='Sandbox_reserved_394/Compound_1/5'>carboxyilic acid portion binds near Gly 142</scene> of Bcl-xl. The carboxylic acid is later substituted with an acyl sulfonamide (shown in compounds 2 & 3) which provides increased affinity.
+<scene name='Sandbox_reserved_394/Compound_1/2'>Compound 1</scene> is a 4'-fluoro-biphenyl-4-carboxylic acid. SAR by NMR was used to identify the interactions that this compound forms with Bcl-xl. The fluorobiphenyl system is hydrophobic and its interactions form a <scene name='Sandbox_reserved_394/Compound_1/4'>"hydrophobic pocket"</scene> around the fluorobiphenyl system. The <scene name='Sandbox_reserved_394/Compound_1/5'>carboxyilic acid portion binds near Gly 142</scene> of Bcl-xl. The carboxylic acid is later substituted with an acyl sulfonamide (shown in compound 2) which provides increased affinity.
-<scene name='Sandbox_reserved_394/Compound_2/1'>Compound 2</scene> binds with high affinity to Bcl-xl. However, this affinity was decreased in the presence of human serum albumin (HSA). In order to decrease HSA affinity, and therefore increase Bcl-xl affinity, SAR by NMR was used to modify compound 1 by eliminating key binding groups of compound 1 without affecting Bcl-xl affinity.
+<scene name='Sandbox_reserved_394/Compound_2/1'>Compound 2</scene> binds with high affinity to Bcl-xl. The <scene name='Sandbox_reserved_394/Compound_2/2'>acylsulfonamide portion forms a hydrogen bond with Gly 142</scene>. The substitution of this sulfonamide for the carboxylic acid from compound 1 allows compound 2 to form a much stronger bond with Bcl-xl by bringing the shared acidic proton in closer proximity to GLY 142. The binding affinity of compound 2 for Bcl-xl is greatly reduced in the presence of human serum albumin (HSA). In order to decrease HSA affinity, and therefore increase Bcl-xl affinity, SAR by NMR was used to modify compound 1 by eliminating key binding groups of compound 1 to HSA without affecting Bcl-xl affinity.
 {| class="wikitable collapsible collapsed"
-! scope="col" width="5000px" | Modifying compound 1 to reduce HSA affinity
+! scope="col" width="5000px" | Modifying compound 2 to reduce HSA affinity
 |-
-| scope="col" width="5000px" | this figure
+| scope="col" width="5000px" | Compound 2 has high affinity for Bcl-xl but has an even higher affinity for HSA. For this reason, when HSA is present, compound 2 and similar ligands are more likely to bind to HSA thereby decreasing the amount that can bind with Bcl-xl. In order to decrease the affinity for HSA while maintaining affinity for Bcl-xl, SAR by NMR was used to compare compound 2 with a <scene name='Sandbox_reserved_394/Compound_3/1'>thioethylamino-2,4-dimethylphenyl analogue</scene>, which also has high affinity for HSA. It was found that two hydrophobic portions of compound 2 had very strong hydrophobic interactions with HSA. Therefore, these portions were modified with polar substituents to decrease HSA affinity. To decrease hydrophobicity, the fluorobiphenyl system was substituted with a piperazine ring and a 2-dimethylaminoethyl group was added to the thioethylamino linkage group.
 |}

Fragment-Based Drug Discovery

From Proteopedia

Revision as of 04:19, 30 October 2012

Drug Design: SAR by NMR

Contents

SAR by NMR

ABT-737

How SAR by NMR was used to develop ABT-737

References

Proteopedia Page Contributors and Editors (what is this?)

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