Leucine-rich repeat kinase 2 (LRRK2) has been an actively pursued target for Parkinson's disease (PD) in recent years due to its genetic linkages to familial PD. It has been demonstrated that several LRRK2 mutations, including the most prevalent G2019S mutation, increase LRRK2 kinase activity in vitro and in vivo. Therefore, a potent and selective small molecule LRRK2 inhibitor could provide a potential disease-modifying therapy for PD. To identify diverse small molecule inhibitors that can be used as starting points for lead optimization, we have developed a funnel-based virtual screening workflow that encompasses homology modeling, and ligand- and structure-based computational technologies. We applied this workflow to both in-house as well as commercial compound collections. This virtual screening strategy has led to the discovery of structurally diverse inhibitors with LRRK2 biochemical Ki's ranging from micromolar to single digit nanomolar.

Identification of diverse and potent LRRK2 kinase inhibitors using a funnel-based virtual screening workflow

248th National Meeting (2014)

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