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Contains fulltext : 135932.pdf (Publisher’s version ) (Closed access) Drug-induced cholestasis is a frequently observed side effect of drugs and is often caused by an unexpected interaction with the bile salt export pump (BSEP/ABCB11). BSEP is the key membrane transporter responsible for the transport of bile acids from hepatocytes into bile. Here, we developed a pharmacophore model that describes the molecular features of compounds associated with BSEP inhibitory activity. To generate input and validation data sets, in vitro experiments with membrane vesicles overexpressing human BSEP were used to assess the effect of compounds (50 muM) on BSEP-mediated (3)H-taurocholic acid transport. The model contains two hydrogen bond acceptor/anionic features, two hydrogen bond acceptor vector features, four hydrophobic/aromatic features, and exclusion volumes. The pharmacophore was validated against a set of 59 compounds, including registered drugs. The model recognized 9 out of 12 inhibitors (75%), which could not be identified based on general parameters, such as molecular weight or SlogP, alone. Finally, the model was used to screen a virtual compound database. A number of compounds found via virtual screening were tested and displayed statistically significant BSEP inhibition, ranging from 13 +/- 1% to 67 +/- 7% of control (P < 0.05). In conclusion, we developed and validated a pharmacophore model that describes molecular features found in BSEP inhibitors. The model may be used as an in silico screening tool to identify potentially harmful drug candidates at an early stage in drug development.

The mechanical heterogeneity of biomolecular structures is intimately linked to their diverse biological functions. Applying rigidity theory to biomolecules identifies this heterogeneous composition of flexible and rigid regions, which can aid in the understanding of biomolecular stability and long-ranged information transfer through biomolecules, and yield valuable information for rational drug design and protein engineering. We review fundamental concepts in rigidity theory, ways to represent biomolecules as constraint networks, and methodological and algorithmic developments for analyzing such networks and linking the results to biomolecular function. Software packages for performing rigidity analyses on biomolecules in an efficient, automated way are described, as are rigidity analyses on biomolecules including the ribosome, viruses, or transmembrane proteins. The analyses address questions of allosteric mechanisms, mutation effects on (thermo-)stability, protein (un-)folding, and coarse-graining of biomolecules. We advocate that the application of rigidity theory to biomolecules has matured in such a way that it could be broadly applied as a computational biophysical method to scrutinize biomolecular function from a structure-based point of view and to complement approaches focused on biomolecular dynamics. We discuss possibilities to improve constraint network representations and to perform large-scale and prospective studies. WIREs Comput Mol Sci 2017, 7:e1311. doi: 10.1002/wcms.1311 For further resources related to this article, please visit the WIREs website.

This editorial provides a brief overview of the 12th International Society for Computational Biology (ISCB) Student Council Symposium and the 4th European Student Council Symposium held in Florida, USA and The Hague, Netherlands, respectively. Further, the role of the ISCB Student Council in promoting education and networking in the field of computational biology is also highlighted.