There are lots of papers that use "fragments" or "fragment approaches". I find a lot of computational papers do this, is it because FBDD has won the field, or its sexy? Well, in this paper the authors take an interesting spin on the term fragment. For many targets (particularly PPI), peptides are the only tool to assess binding, or the best binders. However, despite a small vocal minority, I think most people don't consider peptides to be drugs, but instead good starting points. The REPLACE (Replacement with Partial Ligand Alternatives through Computational Enrichment) method is used to identify fragments for the CDK2A system to identify fragment alternatives to N-terminal portions of the peptide and especially the crucial arginine residue. As I say, repeatedly, Your Computation is only as good as your Experimental Follow up.
This group took a very cautious approach to the initial modeling, understanding that PPIs are difficult to study via computational methods. They used crystal structures of FLIPs (Fragment Ligated Inhibitory Peptides) and modeled in the compounds against subunit B and D. Subunit B gave better results and so that was used for further modeling. [I hate this kind of stuff, strikes me as wrong.] After further work, they concluded that the modeling was validated and would be predictive for new compounds. Then designed a library based on a pharmacophore model using scaffolds phenylacetate, five member heterocycles, and picolinates.
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| Modeled Compounds. Cyclin residues have three letter code, peptides one letter codes. The solid lines show interactions between acidic cyclin D1 residues and the piperinzinylmethyl group of the inhibitor. |
They then, bless their hearts, made some compounds.
In the end, they showed that it is possible to turn peptides into small molecule-ish compounds. Please note these activities are in millimolar! So, even with the current debate as to what PPI fragments should look like, I find it very hard to believe that these molecules are in anyway fragments. Grafting a fragment looking something onto a big something is not "Fragment based Discovery".
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