Identifying target proteins responsible for toxic effects of xenobiotics - Rational Design of Animal Testing

SPILLO-PBSS can be used to search large protein databases for the potential targets of a xenobiotic to predict and/or to clarify the mechanism of toxicity at biomolecular level.

The structural coverage of the human proteome is rapidly increasing, reaching the scale of the proteome, and it is on its way to saturation in the near future.[1] SPILLO-PBSS^[2] can be used to identify the target proteins responsible for toxic effects of any small molecule (e.g., a xenobiotic) on a proteome-wide scale, by screening and ranking the whole available structural proteome of Homo sapiens and other organisms (66,550+ protein 3D-structures, April 2022).

Unlike traditional structure-based approaches (e.g., molecular docking simulations), SPILLO-PBSS includes a suitably designed flexibility which allows an effective identification of the target proteins through their binding sites, which are successfully recognized even within strongly distorted protein conformations (see Comparison with other tools).

A deeper understanding of the molecular mechanisms of action of xenobiotics leads to many advantages in toxicology, among which an improved rational design of experiments on animal models, according to the 3Rs principle (> Read more).

REFERENCES:

[1] J. C. Somody et al., Structural coverage of the proteome for pharmaceutical applications. Drug Discovery Today (2017); DOI: 10.1016/j.drudis.2017.08.004

[2] A. Di Domizio et al., SPILLO-PBSS: Detecting hidden binding sites within protein 3D-structures through a flexible structure-based approach. J. Comput. Chem. (2014); DOI: 10.1002/jcc.23714