In this article we presented a combinatorial docking algorithm based on the incremental construction method in FlexX. The idea of the algorithm is to enumerate the library molecules during the incremental construction algorithm, based on a tree data structure allowing to reuse previously calculated docking results efficiently. Because we assume that the structure of the library is given, the main application of this algorithm is in the development of focussed libraries in cases where already some information about the protein and putative ligands is available.

We applied the new algorithm to three different libraries. For two libraries, we compared the sequential versus the combinatorial docking results showing that they are in good agreement. Nevertheless, it is also shown that the results depend on the order in which the R-groups are added in the build-up procedure. For the third library, we demonstrated that the algorithm is able to retrieve a known inhibitor from a large virtual library.

Because the docking algorithm enumerates the library on the fly, the algorithm is very time- and space-efficient. The calculations for a large library could be done basically in main memory. Compared to a sequential calculation, the combinatorial docking algorithm is 25 to 30 times faster allowing the docking of a 20000-molecule library on a single CPU in a day.

The recursive combinatorial docking algorithm can be applied in cases where one group plays a dominant role in the binding process. This group can be the core or one of the R-groups, it can have several instances and also several different binding modes. If such a group does not exist, the algorithm can still be applied with different build-up orders.

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