Rapid virtual screening of potential PDE 4/5 inhibitors combining 2D/3D similarity search (IJC/Screen), Biological evaluation
2D fingerprint-based similarity search is certainly the fastest and most robust ligand-based approach to select focused libraries from multi-million compound repositories based on the structure of known biologically active compounds. Even though the hit rate often reaches 2-5% further improvement is required. One of the standard methods is to filter the similarity search results according to the calculated physico-chemical parameter space of the known active agents. Another ligand-based approach is to determine the shape/flexibility similarities of the 2D search results towards the known actives and such values can be used for ranking and filtering the 2D similarity results. This novel tool, Screen3D, allows fully flexible matching and can also align flexible database compounds to rigid query molecules using on-the-fly generated conformation ensembles.
Two types of 3D similarity screening methods are available in Screen3D: “Shape” and “Match”. While “Shape” evaluates full molecular shape similarity measures that can model ligand binding to a protein’s active site, “Match” intends to explore key atoms in ligand binding while the actual shape of the molecule is not considered.
In our studies we applied the „Match” function analyzing a previous phosphodiesterase 5 (PDE5) 2D similarity search and screening campaign in order to identify 3D similarity threshold. For 2D similarity search using Instant JChem we set the similarity threshold to 0.65 Tanimoto coefficient. For the first screening round we identified 0.35 cut-off values for Screen3D while for the second round screening using close analogs 0.5 was determined (while 2D similarity values where over 0.8 Tanimoto). In order to validate our results we applied the 0.35 values for refinement of a completely new 2D similarity search generating PDE4 focused libraries.
In our presentation the PDE5 analysis, the selection of the PDE4 focused library and its biological evaluation will be presented.