Growing fragments in silico with FastGrow

Growing fragments is probably the most common approach to improving affinity, and it is immeasurably faster to do this virtually than experimentally. But as anyone who has ever tried can attest, this is often easier said than done. In a new open-access J. Comput. Aided Mol. Des. paper, Matthias Rarey and collaborators at Universität Hamburg, Servier, and BioSolveIT describe a free tool to help.

 

The application is called FastGrow, and it can be accessed through this web server or the SeeSAR 3D software package. It relies on the “Ray Volume Matrix (RVM) shape descriptor,” which simplifies chemical fragments and protein binding pockets into three-dimensional shapes. This allows extremely rapid assessments of whether a given fragment can fit into a binding pocket. A scoring function called JAMDA assesses interactions beyond simple shapes, such as hydrogen bonds and hydrophobic contacts, and also allows fragments to shift slightly to optimize complementarity with the protein.

 

One nice feature of FastGrow is that users can input fragments into multiple binding sites with different amino acid conformations, allowing for protein flexibility. You can also specify an important interaction, such as a critical hydrogen-bond, that you prefer to maintain.

 

To validate the approach, the researchers turned to the database PDBbind and looked for examples in which two ligands with identical cores but different substituents bound to the same protein. They chopped off the substituents from the first ligand and used the resulting fragment as a starting point to try to grow the second ligand. Running 425 of these took just 3 and a half hours and successfully recapitulated the binding mode 71% of the time. This was higher than the popular program DOCK (version 6.9), which seemed to be a pleasant surprise. They attribute the difference to a higher clash tolerance for FastGrow in the initial stages.

 

For additional validation, the researchers turned to real-world examples of fragment-growing for the kinases DYRK1A/B, which we highlighted last year (here and here). Here too FastGrow outperformed DOCK and was also about five-fold faster when using JAMDA (and 600-times faster without JAMDA, though at some cost in performance).

 

FastGrow looks to be a valuable tool, and indeed the researchers note that it is currently in use at Servier. There is a lot more detail in the paper and supplementary materials, including the full code for the FastGrow web server and all the underlying data. It would be interesting to compare its performance to the V-SYNTHES approach we highlightedearlier this year.

 

If you have experience using FastGrow, please leave a comment!