In RIDE, how can I preserve certain regions of the reference molecule while allowing other parts to vary—for example, for a scaffold-hopping application?

[Andrew Orry]

Q: In RIDE, how can I preserve certain regions of the reference molecule while allowing other parts to vary—for example, for a scaffold-hopping application?

A: In RIDE, you can control which parts of the reference molecule are preserved during screening by adjusting the occupancy values assigned to atoms.

• Higher occupancy values (e.g., 1.0) tell RIDE that a region is important and should be preserved during the APF alignment.

• Lower occupancy values (e.g., 0.1) indicate that a region is flexible and can vary in the alignment. 

• We would recommend using 0.1 as the minimum value through to 1.0 as the maximum. 

If you want to fix specific functional groups—such as hydrogen bond donors/acceptors or hinge-binding motifs—assign those atoms an occupancy of 1.0. This will ensure that RIDE maintains those features while exploring new cores that match the overall 3D pharmacophore.

This method is ideal for scaffold-hopping and pharmacophore-focused screening where key interactions need to be retained.