The risk of low selectivity usually represents a serious problem when designing new bioactive molecules; particularly, because similar binding sites could appear even within proteins sharing low sequence and/or structural homology.
On these grounds, the possibility to predict off-target interactions of a therapeutic agent, starting from a well-defined reference binding site, could be of significant support in the Drug Discovery and Development process.
The innovative software SPILLO-Potential Binding Sites Searcher (SPILLO-PBSS 1 ) will be presented. Unlike the case of traditional structure-based approaches, SPILLO-PBSS is able to detect potential binding sites within protein 3D-structures, even when these are highly distorted compared to a suitable binding conformation. In this way the risk of missing potentially relevant off-target proteins is greatly reduced. Morover, SPILLO-PBSS is fast enough for use even on a proteome-wide scale, with relatively limited computational resources, thus representing a valuable support at many stages of Drug R&D (prediction and/or clarification of side effects, polypharmacology, drug repositioning).
According to the "bring your own problems" concept, the participants have the possibility of evaluating (feasibility studies) the use of SPILLO-PBSS to solve their own specific research problems.
Then, they have the opportunity to launch virtual screenings of the whole human structural proteome available (14,000+ protein 3D-structures, without sequence redundancies, from the Protein Data Bank (PDB)) or of the protein database of other organisms of interest (e.g. Plasmodium falciparum), and to retrieve the results at a later date.
1) A. Di Domizio et al (2014). SPILLO-PBSS: Detecting hidden binding sites within protein 3D-structures through a flexible structure-based approach. J. Comp. Chem. 35 (27): 2005-2017.