Patrick C. Maass, Tanja Schulz-Gasch, Martin Stahl, and Matthias Rarey

We present a novel approach for scaffold hopping, called ReCore.

Given a spatial arrangement of two or more exit vectors as well as additional pharmacophore-type search constraints, ReCore is able to detect molecular fragments fulfilling queries with low geometric deviations.

For 3D fragment generation, a new technique is used to exploit conformational information of crystal structures by combining RECAP-like fragmentation with combinatorial enumeration of molecule components. Based on this idea, we developed an algorithm utilizing a geometric rank search approach. The algorithm finds fragments fulfilling all query constraints ordered by increasing deviation.

The new approach has been validated with different design scenarios in which we could demonstrate that ReCore is able to find known linker motifs and new valid scaffold topologies. The used indexing scheme and search technique lead to short response times in the range of seconds