Docking tools to predict whether and how a small molecule binds to a target can be applied if a structural model of such target is available. The reliability of docking depends, however, on the accuracy of the adopted scoring function (SF). Despite intense research over the years, improving the accuracy of SFs for structure‐based binding affinity prediction or virtual screening has proven to be a challenging task for any class of method. New SFs based on modern machine‐learning regression models, which do not impose a predetermined functional form and thus are able to exploit effectively much larger amounts of experimental data, have recently been introduced. These machine‐learning SFs have been shown to outperform a wide range of classical SFs at both binding affinity prediction and virtual screening. The emerging picture from these studies is that the classical approach of using linear regression with a small number of expert‐selected structural features can be strongly improved by a machine‐learning approach based on nonlinear regression allied with comprehensive data‐driven feature selection. Furthermore, the performance of classical SFs does not grow with larger training datasets and hence this performance gap is expected to widen as more training data becomes available in the future. Other topics covered in this review include predicting the reliability of a SF on a particular target class, generating synthetic data to improve predictive performance and modeling guidelines for SF development. WIREs Comput Mol Sci 2015, 5:405–424. doi: 10.1002/wcms.1225For further resources related to this article, please visit the WIREs website.

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with different (from 0 to 6) combinations of truncated and full-length sequences. Formation of concatemers was assessed by the use of singlemolecule photobleaching and protein cross-linking. Whole-cell recordings from concatenated PANX1 constructs suggest that at least four intact C-termini are required to inhibit channel activity. In addition, as the number of intact C-termini increased, there was a progressive decrease in single channel conductance, suggesting that individual C-termini may act within the multimeric channel to inhibit channel conductance. These results provide further mechanistic insights into the regulation of PANX1 channels by the C-terminal autoinhibitory domains.