Schrödinger - Phase Shape: A fast and efficient tool for shape-based superposition and similarity searching

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Phase Shape

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A series of CDK2 inhibitors aligned by Phase Shape. Compounds were flexibly positioned atop the bound conformation of the ligand from PDB structure 2g9x (shown in space-filing mode). Common structural motifs show excellent alignment across the test set.

Phase Shape: A fast and efficient tool for shape-based superposition and similarity searching

Phase Shape is capable of screening large databases of compounds to identify new leads with similar shape and electrostatic properties to a lead query molecule. The method has been described and validated in a publication in the Journal of Chemical Information and Modeling.

The Advantage of Phase Shape

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.

Phase Shape is an effective tool for lead optimization studies, where rapid flexible superposition of multiple similar molecules is essential to understanding SAR. Phase Shape is also ideally suited for use in the early stages of lead discovery. Phase Shape 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.

Phase Shape can run in shape-only mode, or it can incorporate atom-type similarity when aligning and scoring. Phase Shape 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.

Works to Cite

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

Features

Speed and performance:
Phase Shape 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:
Phase Shape 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.

Intuitive overlays:
A benefit of Phase Shape’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:
Phase Shape 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. Phase Shape relies on the well-validated program ConfGen.²

Superior enrichments:
As a result of its unique capacity to align pharmacophore features, Phase Shape outperformed competing shape-based methods in virtual database screens involving 11 diverse targets and 25,000 decoys.¹ Phase Shape 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.
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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.