An integrated workflow for proteome-wide off-target identification and polypharmacology drug design

Polypharmacology, which focuses on designing drugs to target multiple receptors, has emerged as a new paradigm in drug discovery. To rationally design multi-target drugs, it is fundamental to understand protein-ligand interactions on a proteome scale. We have developed a Proteome-wide Off-target Pip...

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Bibliographic Details
Main Authors: Evangelidis, T., Li Xie, Bourne, Philip E.
Format: Conference Proceeding
Language:English
Subjects:
Drug discovery
Drugs
Electric potential
Electrostatics
Human immunodeficiency virus
Humans
Inhibitors
off-target
polypharmacology
Proteins
structural proteomics
systems biology
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Summary:Polypharmacology, which focuses on designing drugs to target multiple receptors, has emerged as a new paradigm in drug discovery. To rationally design multi-target drugs, it is fundamental to understand protein-ligand interactions on a proteome scale. We have developed a Proteome-wide Off-target Pipeline POP that integrates ligand binding site analysis, protein-ligand docking, the statistic analysis of docking scores, and electrostatics potential calculation. The utility of POP is demonstrated by a case study, in which the molecular mechanism of anti-cancer effect of Nelfinavir is hypothesized. By combining structural proteome-wide off-target identification and systems biology, it is possible for us to correlate drug perturbations with clinical outcomes.
DOI:10.1109/BIBMW.2012.6470348