A fast and efficient tool for shape-based superposition and similarity searching
A series of CDK2 inhibitors aligned by Shape Screening are shown against a bound conformation depicted in CPK spheres. Common structural motifs show excellent alignment across the test set.
Shape Screening: A fast and efficient tool for shape-based superposition and similarity searching
Shape Screening 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 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.
