Annuaire
Rational Prediction of PROTAC-Compatible Protein-Protein Interfaces by Molecular Docking.
J Chem Inf Model, 63(21):6823-6833.
Proteolysis targeting chimeras (PROTACs) are heterobifunctional ligands thatmediate the interaction between a protein target and an E3 ligase, resulting in aternary complex, whose interaction with the ubiquitination machinery leads totarget degradation. This technology is emerging as an exciting new avenue fortherapeutic development, with several PROTACs currently undergoing clinicaltrials targeting cancer. Here, we describe a general and computationallyefficient methodology combining restraint-based docking, energy-based rescoring,and a filter based on the minimal solvent-accessible surface distance to producePROTAC-compatible PPIs suitable for when there is no a priori known PROTACligand. In a benchmark employing a manually curated data set of 13 ternarycomplex crystals, we achieved an accuracy of 92% when starting from boundstructures and 77% when starting from unbound structures, respectively. Ourmethod only requires that the ligand-bound structures of the monomeric forms ofthe E3 ligase and target proteins be given to run, making it general, accurate,and highly efficient, with the ability to impact early-stage PROTAC-based drugdesign campaigns where no structural information about the ternary complexstructure is available.
Actions sur le document
