SiteAlign. We performed an all-against-all comparison using the pocket comparison method SiteAlign 18 (version 4.0). In this approach, properties of a binding site are projected to a triangulated sphere positioned at the pocket center, stored as a fingerprint to be compared and aligned to another binding site fingerprint iteratively. Since we used the existing KLIFS alignment, a few SiteAlign parameters were adapted to reduce runtime: we decreased the number of alignment steps in SiteAlign from 3 to 1, the translational steps from 5 to 3, and reduced the rotational and translational intensity from 2π to π and from 4 to 1, respectively. Comparison of the SiteAlign performance for > 4000 structure pairs with the default and adjusted settings, showed that the adjusted settings resulted in lower distances (average decrease of 6%), while matching a higher number of triangles (average increase of 15%). Pocket residues with modifications (e.g. phosphorylated threonines) were excluded to avoid segmentation faults.