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Fragment-Based Drug Discovery

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Ligand-Based Drug Design: SAR by NMR

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 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 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."^[2] This is the process of 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, and , are very similar in structure and contribute many of the same groups needed for high affinity. Coumpound 2 is an acylsulfonamide-based ligand while compound 3 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"

@@ Line 16: / Line 16: @@
 ===== Precursors to ABT-737 =====
-Several ligands were discovered to have moderate affinity for Bcl-xl. Using SAR by NMR, each of these precursors were analyzed for structural components and functional groups that are critical for Bcl-xl affinity.
+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.
-Using the example of ABT-737
-<scene name='Sandbox_reserved_394/Compound_1/1'>Compound 1</scene> 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>. The fluorobiphenyl system is significant to the high affinity of ABT-737. 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 two subsequent compounds. Notice the stability of the biphenyl system. 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).
-<scene name='Sandbox_reserved_394/Compound_2/1'>Compound 2</scene> and <scene name='Sandbox_reserved_394/Compound_3/1'>Compound 3</scene> are very similar in structure and contribute many of the same groups needed for high affinity. Coumpound 1 is an acylsulfonamide-based ligand while compound 2 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 they also 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.
+<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.
-SAR by NMR is also useful for analyzing a drug target to obtain a better understanding of its function and activity as well as identifying similar targets. For example, Bcl-2 and Bcl-w are proteins that were discovered to have structures very closely related to Bcl-xl as well as similar roles as anti-apoptotic proteins.
+The other precursors, <scene name='Sandbox_reserved_394/Compound_2/1'>compound 2</scene> and <scene name='Sandbox_reserved_394/Compound_3/1'>compound 3</scene>, are very similar in structure and contribute many of the same groups needed for high affinity. Coumpound 2 is an acylsulfonamide-based ligand while compound 3 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>
-=== Bcl-xl: a member of the Bcl-2 family ===
-----
-<scene name='Sandbox_reserved_394/Bcl-xl/1'>Bcl-xl</scene> is a member of the Bcl-2 family.  The protein is comprised of seven <scene name='Sandbox_reserved_394/Alpha_helices/1'>alpha helices</scene>, no beta sheets, and 221 amino acid residues.
-==== Bcl-xl Inhibition with ABT-737 ====
-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/>

Fragment-Based Drug Discovery

From Proteopedia

Revision as of 02:24, 24 October 2012

Ligand-Based Drug Design: SAR by NMR

Contents

SAR by NMR

ABT-737

Precursors to ABT-737

References

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