Scientific advances regarding drugs targeting Protein-Protein Interactions (PPIs) suggest that this challenge is becoming less daunting and should lead to successes in the very next years. Technological and conceptual advances in understanding and predicting druggability have permitted this breakthrough. Other impediments are still there. Among them, the improvement of compounds selection dedicated to PPIs chemical space represents an exciting challenge for the chemoinformatics community. We have recently developed to that matter 2P2IHUNTER, a tool for filtering potential orthosteric PPI modulators via a dedicated support vector machine. In the present research article we applied our algorithm to 8.3 million compounds representing the main chemical providers commercially available, to design a PPI-focused library, 2P2IREF composed of 143,218 small molecules. Compounds corresponding to medicinally important privileged structures identified as core structures in numerous therapeutics were prioritized in a medicinal oriented version of this database (2P2IPRIV - 51,476 compounds). A diverse chemical library was generated using 2D molecular fingerprints (2P2IDIV - 8,217 diverse compounds). The carbon bond saturation index (Fsp3) was used as a final filter (Fsp3 ≥ 0.4) to escape from flatland, another hurdle in the long path to the gold mine. We analyzed the resulting chemical space of this final library of 1,683 compounds, 2P2I3D and discuss the chemical moieties proposed to the community. This library will now be tested to evaluate its ability to enhance hit rates in general screening campaigns and is open to academic and private companies for collaborative prospects.

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