Our method aims to substitute fragments of the inhibitor while leaving the rest of the inhibitor as its original conformation as design template. This approach is based on a set of fragment scores of docked inhibitors. To find the potential active compounds, known inhibitors are generated through virtual screening and further docked into the receptor active site. By applying our defined fragmentation schemes, each inhibitor is regarded as a composition of several fragments. With binding information, multi-objective scoring function is applied for each fragment. The fragment score is calculated through force-field energy interaction in the binding site and fingerprints of fragment properties. Fragment hopping can be promoted by tuning the relative weights of these terms in the scoring function. The undesirable scores of fragments from the inhibitor serve as query fragments and undergo fragment hopping with a ranked database of predocked fragments. The predocked fragments are a collection of synthesizable docked molecular building blocks. To consider the geometry conformation, the connection rule for the new upcoming fragment is applied during fragment hopping. Finally, new compounds are energy minimized and confirmed with docking method. To validate our approach, a case study with the Human 5-LOX enzyme active site is investigated and its interaction with the suggested new inhibitors is analyzed.

Structure-based fragment hopping ligand design using predocked fragment database

240th National Meeting (2010)

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