Recent advances in computational chemistry techniques paired with the availability of powerful hardware solutions, have contributed establishing Virtual Screening (VS) as an increasingly popular tool in drug discovery.<br/>Here, we describe a VS protocol aimed at identifying inhibitors of the Signal Transducer and Activator of Transcription 5 (STAT5), a validated target for pharmacological intervention in a number of human malignancies, including prostate cancer, breast cancer and hematologic disorders.<br/>Our method benefits from combining recent and state-of-the-art techniques in a multi-step implementation that relies on both ligand- and receptor-based screening. We used Fragment-Based Shape Signatures, a screening method developed in our laboratory, for pre-filtering very large compound collections. Then, we applied molecular docking of screening hits against a STAT5 model in complex with a phosphopeptide ligand and we performed hit reconfirmation by MMGBSA and FEP calculations. Finally, we used per-residue interaction scores and principal component analysis to prioritize candidate molecules for in vitro validation.<br/>Our results contribute to establish VS as an effective tool in modern drug discovery, and provide useful insights for rationally designing novel STAT5 inhibitors.

Ligand- and receptor-based virtual screening for inhibitors of the signal transducer and activator of transcription 5 (STAT5)

253rd National Meeting (2017)

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