Fragment-Based Drug Discovery: Difference between revisions

The development of <scene name='Sandbox_reserved_394/Abt-737/2'>ABT-737</scene> using SAR by NMR is a classic example of FBDD. (Throughout this discussion ABT-737 will be used to illustrate the FBDD process.) This compound has been shown to effectively inhibit the over-expression of <scene name='Sandbox_reserved_394/Bcl-xl/1'>Bcl-xl</scene> which is a protein that is commonly observed to be over-expressed in many types of cancers.<ref name="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">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</ref> 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.

<scene name='Sandbox_reserved_394/Compound_1/7'>Two fragments</scene> were found to have moderate affinity for Bcl-xl. <scene name='Sandbox_reserved_394/Compound_1/9'>Compound 1</scene> is a fluorobiphenylcarboxylic acid. It occupies <scene name='Sandbox_reserved_394/Binding_site_1/2'>binding site 1</scene> of Bcl-xl which consists of Phe 101, Tyr 105, Ala 108, Phe 109, Leu 136, Gly 142, Arg 143, and Ala 146. The fluorobiphenyl system of compound 1 is very hydrophobic and therefore, these residues form a <scene name='Sandbox_reserved_394/Compound_1/4'>"hydrophobic pocket"</scene> around the system. There is also one hydrophilic interaction involved in this complex. The <scene name='Sandbox_reserved_394/Compound_1/5'>carboxylic acid portion of compound 1 binds near Gly 142</scene> of Bcl-xl. This is not a strong interaction but is significant because it can be modified to form a much stronger bond.