ProBiS-Dock: A Hybrid Multitemplate Homology Flexible Docking Algorithm Enabled by Protein Binding Site Comparison

The protein data bank (PDB) is a rich source ofprotein ligand structures, but ligands are not explicitly used incurrent docking algorithms. We have developed ProBiS-Dock, adocking algorithm complementary to the ProBiS-Dock Database(J. Chem. Inf. Model.2021, 61,4097-4107) that treats smallmolecules and proteins as fullyflexible entities and allowsconformational changes in both after ligand binding. A newscoring function is described that consists of a binding site-specificscoring function (ProBiS-Score) and a general statistical scoringfunction. ProBiS-Dock enables rapid docking of small molecules toproteins and has been successfully validated in silico againststandard benchmarks. It enables rapid search for new active ligands by leveraging existing knowledge in the PDB. The potential ofthe software for drug development has been confirmed in vitro by the discovery of new inhibitors of human indoleamine 2,3-dioxygenase 1, an enzyme that is an attractive target for cancer therapy and catalyzes thefirst rate-determining step ofL-tryptophanmetabolism via the kynurenine pathway. The software is freely available to academic users athttp://insilab.org/probisdock.