Incorporating computational effort within medicinal chemistry has become an established strategy to accelerate individual stages of drug discovery (Jorgensen, Science 2004 ). However, the effectiveness of combining approaches that are highly optimized for specific workflows is not always guaranteed. Here, we describe a strategy to integrate shape-based recognition (Zauhar et al., J. Comput. Aided Mol. Des. 2013 ) with molecular dynamics as essential components of hit identification, as well as lead identification and optimization.We used our approach to aid multiple stages of the search for small molecule inhibitors of three proteins involved in human disease. First, we validated our strategy using the androgen receptor (AR), a well studied oncological target. We then focused on the signal transducer and activator of transcription 5 (STAT5), a human protein essential in prostate cancer development and progression. Lastly we study the M2 proton channel, an integral membrane protein of the influenza virus, which poses significant challenges to rational drug design due to the role played by water molecules in molecular recognition (Wang et al., PNAS 2013 ).

Combining shape-based recognition and molecular simulation in drug discovery

248th National Meeting (2014)

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