Fragment-Based Drug Discovery: Difference between revisions

The development of <scene name='Sandbox_reserved_394/Abt-737/1'>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.

| 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.