A fast and efficient tool for shape-based superposition and similarity searching
The Advantage of Shape Screening
The goal of shape-based screening is simple and straightforward: Given the structure and shape of a compound known to bind to a target, shape-based screens will identify new compounds with shapes (and, if desired, other properties) that are similar to the known binder. The approach is consistent with physical chemistry intuition: a receptor "sees" the shape and electrostatic properties of a molecule that binds to it, so if a new compound matches the shape and electrostatic properties of a known binder then it is likely to bind as well.
Shape Screening is an effective tool for lead optimization studies, where rapid flexible superposition of multiple similar molecules is essential to understanding SAR. Shape Screening is also ideally suited for use in the early stages of lead discovery. Shape Screening does not require a target crystal structure or well-developed SAR sets that might be necessary to create a reliable pharmacophore model. Only a single known active query compound is needed.
Shape Screening can run in shape-only mode, or it can incorporate atom-type similarity when aligning and scoring. Shape Screening also includes a unique mode that describes each structure as a collection of pharmacophore features rather than individual atoms. This pharmacophore-based mode produces the highest database enrichments.
Speed and performance:
Shape Screening can screen approximately 600 conformers per second and has been shown to outperform other shape-based methods in virtual screening enrichment studies for a wide range of targets.1
A novel method for aligning compounds:
Shape Screening uses pairwise atom distance distributions to identify atom triplets that afford rapid trial alignments between the query compound and the structures being screened. The best trial alignments are subjected to a refinement step that improves the overall superposition and maximizes shape similarity.
A benefit of Shape Screening’s alignment algorithm is that common scaffolds will in most cases be neatly overlaid (see image above) – as one would expect in a series of structurally similar lead compounds.
Rapid determination of shape similarity:
Shape Screening uses an empirically verified model of shape similarity, wherein molecular volumes are approximated using rapidly calculated sums of pairwise atomic overlaps.
Efficient generation of bioactive conformers:
Conformer generation is a necessary component of any shape-based screening algorithm. Shape Screening relies on the well-validated program ConfGen.2
As a result of its unique capacity to align pharmacophore features, Shape Screening outperformed competing shape-based methods in virtual database screens involving 11 diverse targets and 25,000 decoys.1 Shape Screening yielded an average enrichment factor in the top 1% (EF(1%)) of 33.2, compared to 25.6 and 23.5 for ROCS-Color and SQW, respectively.
1Sastry, G.M.; Dixon, S.L.; Sherman, W., "Rapid Shape-Based Ligand Alignment and Virtual Screening Method Based on Atom/Feature-Pair Similarities and Volume Overlap Scoring," J. Chem. Inf. Model., 2011, 51, 2455-2466
2Watts, K.S.; Dalal, P.; Murphy, R.B.; Sherman, W.; Friesner, R.A.; Shelley, J.C.; "ConfGen: A Conformational Search Method for Efficient Generation of Bioactive Conformers," J.Chem. Inf. Model., 2010, 50, 534-546.
Citations and Acknowledgements
Schrödinger Release 2016-4: Phase, Schrödinger, LLC, New York, NY, 2016.
ö Sastry, G.M.; Dixon, S.L.; Sherman, W., "Rapid Shape-Based Ligand Alignment and Virtual Screening Method Based on Atom/Feature-Pair Similarities and Volume Overlap Scoring," J. Chem. Inf. Model., 2011, 51, 2455-2466