Training Workshop: In Silico Methods in Hazard Identification
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. 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), 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.
 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
 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
 SPILLOproject website: www.spilloproject.com