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Fragment-Based Drug Discovery: Difference between revisions

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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'>
In many forms of cancer, a family of proteins, known as the BCL-2 family, has been observed as being over-expressed. This over-expression prevents apoptosis from occurring and may also contribute resistance to chemotherapy.
In many forms of cancer, a family of proteins, known as the BCL-2 family, has been observed as being over-expressed. This over-expression prevents apoptosis from occurring and may also contribute resistance to chemotherapy.
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=== ABT-737 ===
=== ABT-737 ===
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<scene name='Sandbox_reserved_394/Abt-737/1'>ABT-737</scene>  
<scene name='Sandbox_reserved_394/Abt-737/1'>ABT-737</scene> has been shown to effectively inhibit the over-expression of the Bcl-2 family of proteins, and thus allowing apoptosis to occur and preventing chemo-resistance. This compound has very high affinity for <scene name='Sandbox_reserved_394/Bcl-xl/1'>Bcl-xl</scene>, which is a specific protein of the Bcl-2 family.
 
=== Bcl-xl: a member of the Bcl-2 family ===
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<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 .
 
ABT-737 is not a naturally occurring compound but is a result of ligand-based design using SAR by NMR. 


=== Ligand-Based Design ===
=== SAR by NMR ===
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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. This process is known as ligand-based design. The use of this method has resulted in the discovery and production of many medicinal agents available for phramacologic therapy.
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. This process is known as ligand-based design. The use of this method has resulted in the discovery and production of many medicinal agents available for phramacologic therapy, including 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."<ref>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> Using this tool 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.
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."<ref>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> Using this tool 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.


Discovering ABT-737 involved a process of analyzing a series of precursors to the final ligand. Several compounds were found to have affinity for Bcl-xl. Using SAR by NMR, each of these precursors were analyzed for functional groups that were critical for high affinity binding.
Discovering ABT-737 involved a process of analyzing a series of precursors to the final ligand. Several compounds were found to have affinity for Bcl-xl. Using SAR by NMR, each of these precursors were analyzed for functional groups that were critical for high affinity binding.
For example:


<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_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).
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<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_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.


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.</StructureSection>
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.
   
   
=== Bcl-xl: a member of the Bcl-2 family ===
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<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 . </StructureSection>
= References =
= References =
{{Reflist}}
{{Reflist}}

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Arthur Cox, Justin Weekley, Jaime Prilusky
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