The co-crystallized ligands in Protein Data Bank (PDB) represent a great quantity of information about protein binding sites. There are more than 100,000 ligands all-together and more than 20,000 unique ligands in the PDB; however, this information is not used explicitly in the existing docking algorithms. Docking has had persistent problems in predicting binding free energies and related to that scoring and ranking of docked poses is still an open problem. We developed ProBiSdock, a docking algorithm that scores the docked poses using unique new scoring function in which the pose’s score depends on its overlap with the existing ligands' atom field. This force field is generated for each query protein specifically from existing co-crystallized ligands in other protein structures in the PDB transposed to the query protein using ProBiS binding sites alignment algorithm. To account for conformational changes in protein upon ligand binding, both compounds and proteins are treated as flexible. ProBiSdock enables fast docking of large databases containing millions of compounds and has been successfully validated on the DUD-E benchmark, on cross-docking examples where the treatment of protein flexibility is required, as well as it was used to discover new experimentally confirmed inhibitors of IDO-1 enzyme, an attractive target in cancer therapy. ProBiSdock enables medicinal chemists to quickly search for new active compounds taking into account existing knowledge in the PDB and has been successfully validated in silico and in vitro.

ProBiSdock: Flexible docking using existing knowledge from the Protein Data Bank

255th National Meeting (2018)

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