An Ensemble of Virtual Screening Methods Proves Successful

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blue molecule model

The identification of lead molecules showing pharmacological activity against a biological target is a key focal point of early-stage drug discovery. Virtual screening can play a vital role by finding novel hits early in the drug discovery process and has proven to be an invaluable tool in supporting fast and cost-efficient lead discovery.

The combination of ligand- and structure-based virtual screens can be a positive integrated hit finding approach as demonstrated in targeting LRRK2, a member of the leucine-rich repeat kinase family associated with an increased risk of Parkinson’s disease. A recent paper by Gancia, et al. published in Bioorganic & Medicinal Chemistry Letters describes a successful virtual screen (VS) against the kinase LRRK2 that provided tractable starting points for a hit optimization program.

According to the authors, the ligand-based virtual screen used the structures of competitor compounds as queries for a variety of 2D and 3D searches while the structure-based screen relied on homology models of LRRK2. From there, hundreds of compounds from the virtual screen were then tested, leading to the identification of 35 hits, 4 of which were deemed to have potential for medicinal chemistry follow-up. With this success, the use of combined ligand- and structure-based virtual screening can be considered as an option when designing certain hit finding approaches.