Fragment-Based Drug Discovery
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Apoptosis by Inhibition of Bcl-2 Family ProteinsApoptosis by Inhibition of Bcl-2 Family Proteins
Apoptosis, or programmed cell death, is a natural mechanism in which a damaged cell dies in order to prevent further damage to the multicellular organism. The absence of apoptosis may occur in damaged cells and can lead to many types of cancers and other diseases. In certain types of cancers, a family of proteins, known as the Bcl-2 family, has been observed as being over-expressed compared to normal, healthy cells.[1] There is also evidence to suggest that Bcl-2 over-expression may also contribute to chemo-resistance.
Bcl-xl: a member of the Bcl-2 familyBcl-xl: a member of the Bcl-2 family
is a member of the Bcl-2 family. The protein is comprised of seven , no beta sheets, and 221 amino acid residues.
Bcl-xl InhibitionBcl-xl Inhibition
Inhibiting the over-expression of this protein has been shown to effectively at induce tumor regression and increase chemo-sensitivity. This can be done with an acylsulfonamide-based ligand such as .
Intermolecular BindingIntermolecular Binding
There are several intermolecular, or "weak", bonds at work to form the complex. This type of bonding is responsible for There is one at work in this complex. The bond is formed between an oxygen from the sulfoxone portion of the drug to an "N-H" group of a glycine amino acid. This forms one of the intermolecular or "weak" bonds between the drug and protein.
Shown here is a sort of formed between the protein (red) and hydrophobic, or "water hating", portions of the acyl-sulfonamide. This is an example of hydrophobic bonding formed by intermolecular forces between some hydrophobic sections of the protein with hydrophobic portions of the ligand.
Click on each amino acid to view the hydrophobic interactions with the ligand:
Rational Drug DesignRational Drug Design
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 rational drug design. This method has resulted in the discovery and production of many medicinal agents available for phramacologic therapy.
SAR by NMRSAR by NMR
One tool used in rational drug 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] 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.
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 were proteins that were discovered to have structures very closely related to Bcl-xl as well as similar roles as anti-apoptotic proteins.
ABT-737ABT-737
Since proteins usually have multiple binding sites, exploring each site gives new insight on designing a ligand with the highest possible affinity. For example, upon analyzing cmpd 1,2,3,4, abt-737 was discovered has been shown to effectively inhibit the over-expression of this protein thereby inducing tumor regression and increasing chemo-sensitivity.
ReferencesReferences
- ↑ 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
- ↑ 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.