MOTIVATION: Many approaches in systems biology have been applied in drug repositioning due to the increased availability of the omics data and computational biology tools. Using a multi-omics integrated network, which contains information of various biological interactions, could offer a more comprehensive inspective and interpretation for the drug mechanism of action (MoA). RESULTS: We developed a computational pipeline for dissecting the hidden MoAs of drugs (Open MoA). Our pipeline computes confidence scores to edges that represent connections between genes/proteins in the integrated network. The interactions showing the highest confidence score could indicate potential drug targets and infer the underlying molecular MoAs. Open MoA was also validated by testing some well-established targets. Additionally, we applied Open MoA to reveal the MoA of a repositioned drug (JNK-IN-5A) that modulates the PKLR expression in HepG2 cells and found STAT1 is the key transcription factor. Overall, Open MoA represents a first-generation tool that could be utilized for predicting the potential MoA of repurposed drugs and dissecting de novo targets for developing effective treatments. AVAILABILITY AND IMPLEMENTATION: Source code is available at https://github.com/XinmengLiao/Open_MoA.

BACKGROUND: Post-translational modifications (PTMs) constitute a major aspect of protein biology, particularly signaling events. Conversely, several different pathophysiological PTMs are hallmarks of oxidative imbalance or inflammatory states and are strongly associated with pathogenesis of autoimmune diseases or cancers. Accordingly, it is of interest to assess both the biological and structural effects of modification. For the latter, computer-based modeling offers an attractive option. We thus identified the need for easily applicable modeling options for PTMs. RESULTS: We developed PyTMs, a plugin implemented with the commonly used visualization software PyMOL. PyTMs enables users to introduce a set of common PTMs into protein/peptide models and can be used to address research questions related to PTMs. Ten types of modification are currently supported, including acetylation, carbamylation, citrullination, cysteine oxidation, malondialdehyde adducts, methionine oxidation, methylation, nitration, proline hydroxylation and phosphorylation. Furthermore, advanced settings integrate the pre-selection of surface-exposed atoms, define stereochemical alternatives and allow for basic structure optimization of the newly modified residues. CONCLUSION: PyTMs is a useful, user-friendly modelling plugin for PyMOL. Advantages of PyTMs include standardized generation of PTMs, rapid time-to-result and facilitated user control. Although modeling cannot substitute for conventional structure determination it constitutes a convenient tool that allows uncomplicated exploration of potential implications prior to experimental investments and basic explanation of experimental data. PyTMs is freely available as part of the PyMOL script repository project on GitHub and will further evolve. Graphical Abstract PyTMs is a useful PyMOL plugin for modeling common post-translational modifications.