Computational Approaches For The Discovery Of Small Molecule Protein-Protein Interaction Inhibitors

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SELECTBIO

Protein-protein interactions (PPIs) are essential in a multitude of biological processes, and are often linked with pathogenicities, thus forming an attractive target for drug discovery. They were once thought to be undruggable, but in recent years, several successes in the design of small-molecule protein-protein interaction inhibitors (SMPPIIs) have been reported. During this presentation the main focus will be on computational methods developed after structural analysis of (and benchmarked with) previously reported SMPPIIs. These methods enable efficient virtual screening for SMPPII as our results indicate. Pharmacophore queries are generated by thoroughly analyzing the structures of the PPI interface, in order to virtually screen for compounds that possess the correct chemical functionalities and geometry to mimic the key interactions of the interface. For post-processing of the virtual screening, we have developed EleKit; a tool that correlates the electrostatic fields of the small molecules with that of the ligand protein. These methods have been successfully employed for the discovery of the small molecule inhibitors of the salmonella PLIC:lysozyme interaction. Another successful application of this method was the design of the first inhibitors of the HIV-1-integrase:LEDGF/p75 interaction: one class targeting the human LEDGF/p75 protein, the other the viral integrase protein. These inhibitors have been licensed to Pfizer for further optimization. Recently, we have identified the very first druglike inhibitors of the SUMO1:SBM interaction, which is a novel attractive target for anti-cancer therapy.