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Open AccessArticle

Extensive Reliability Evaluation of Docking-Based Target-Fishing Strategies

1
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
2
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
3
Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(5), 1023; https://doi.org/10.3390/ijms20051023
Received: 31 January 2019 / Revised: 21 February 2019 / Accepted: 22 February 2019 / Published: 27 February 2019
(This article belongs to the Section Molecular Informatics)
The development of target-fishing approaches, aimed at identifying the possible protein targets of a small molecule, represents a hot topic in medicinal chemistry. A successful target-fishing approach would allow for the elucidation of the mechanism of action of all therapeutically interesting compounds for which the actual target is still unknown. Moreover, target-fishing would be essential for preventing adverse effects of drug candidates, by predicting their potential off-targets, and it would speed up drug repurposing campaigns. However, due to the huge number of possible protein targets that a small-molecule might interact with, experimental target-fishing approaches are out of reach. In silico target-fishing represents a valuable alternative, and examples of receptor-based approaches, exploiting the large number of crystallographic protein structures determined to date, have been reported in the literature. To the best of our knowledge, no proper evaluation of such approaches is, however, reported yet. In the present work, we extensively assessed the reliability of docking-based target-fishing strategies. For this purpose, a set of X-ray structures belonging to different targets was selected, and a dataset of compounds, including 10 experimentally active ligands for each target, was created. A target-fishing benchmark database was then obtained, and used to assess the performance of 13 different docking procedures, in identifying the correct target of the dataset ligands. Moreover, a consensus docking-based target-fishing strategy was developed and evaluated. The analysis highlighted that specific features of the target proteins could affect the reliability of the protocol, which however, proved to represent a valuable tool in the proper applicability domain. Our study represents the first extensive performance assessment of docking-based target-fishing approaches, paving the way for the development of novel efficient receptor-based target fishing strategies. View Full-Text
Keywords: target fishing; docking; reverse screening; consensus docking target fishing; docking; reverse screening; consensus docking
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Lapillo, M.; Tuccinardi, T.; Martinelli, A.; Macchia, M.; Giordano, A.; Poli, G. Extensive Reliability Evaluation of Docking-Based Target-Fishing Strategies. Int. J. Mol. Sci. 2019, 20, 1023.

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