ROCS shape searching

Moffat, K., Gillet, V. J., Whittle, M., Bravi, G., Leach, A. R. (2008) A comparison of field-based similarity searching methods Cat-Shape, FBSS, and ROCS. J Chem Inf Model 48, 719-729. 

ROCS is using a shape-based superposition for identifying compounds that have similar shape. Grant and Pickup (118) showed that using atomic-centered Gaussians instead of a spherical function can dramatically reduce the time required for a shape alignment of two molecules. This improved routine allows the program to perform shape-based database searches at an acceptable speed (300-400 conformers/s). 

A further important option for ligand-based virtual screening is to perform shape comparisons that have a pronounced scaffold hopping potential. An often used method of this kind is ROCS [31] (OpenEye Scientific Sofiware, 9 Bisbee Court Suite D, Santa Fe, NM 87508, USA. Available at http //www.eyesopen.com, March 20, 2009). ROCS employs continuous functions that are derived from atom-centered Gaussians to calculate the volume overlap between two 3D structures. The use of Gaussians drastically speeds up the computational process, and ROCS is able to search even databases with millions of compounds for molecules that can adopt shapes similar to the reference compound. As in the case of 3D pharmacophore searches, the low-energy conformations must be precomputed for the search database. 

The overlay obtained for compound 123 shows a much better shape match to the template with an improved overlay of the aromatics in the bioisosteric head group. However, the acceptor features of the cyclic amide are less convincing, hence the lower rankings (Cresset rank 144 in both searches). The retrospective ROCS analysis ranked this exemplar 308th using the combo score (rank 96 by shape only and 840 by color), so this would have appeared much lower in the ROCS hits. The results summary shows that this monomer was not selected on the basis of the Cresset results but included as part of the additional chemists selection. This was due to the poor match of the FieldPoints around the head group with the reference compound. 

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