Training Workshop: In Silico Methods in Hazard Identification

Training Workshop: In Silico Methods in Hazard Identification

Training Workshop: In Silico Methods in Hazard Identification

SPILLOproject contribution:

TITLE OF THE TALK:   3D proteome-wide scale screening to predict toxic effects by the innovative SPILLO-PBSS software

Structural coverage of the human proteome is rapidly increasing, reaching the scale of the proteome, and on its way to saturation in the near future.[1] Hence, computational tools able to perform in silico screenings of very large protein databases (including thousands of protein 3D-structures) have gained growing interest and attention in all areas where molecular recognition via protein-ligand interactions plays a key role, including toxicology.

A direct identification of target proteins potentially responsible for toxicological effects of xenobiotics is crucial for a deep understanding of their molecular mechanisms of action, leading to many advantages in toxicology, such as a reduction and a better rational design of experiments on animal models.

However, one major drawback of existing fast structure-based approaches (e.g., molecular docking software) is that protein flexibility is not properly taken into account, since they often perform static analyses of just one or a few rigid protein conformations. Therefore, the success of a prediction is often limited to those few lucky situations where the binding site of the xenobiotic is already open and in a suitable conformation for the binding.

In this talk I’ll briefly outline an innovative flexible structure-based approach, SPILLO-Potential Binding Sites Searcher (SPILLO-PBSS),[2][3] with unique potentialities in identifying binding sites of small molecules on protein 3D-structures, whether or not they are occupied, strongly distorted, or even completely closed, compared to a suitable conformation for the binding. SPILLO-PBSS allows a fast identification of target and off-target proteins of any small molecule on a proteome-wide scale (e.g., the whole available structural proteome of homo sapiens or other organisms), with higher probabilities of success when compared to traditional methods.



[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

[3] SPILLOproject website: