Quaternary Complex of human WDR5 and pVHL:ElonginC:ElonginB bound to PROTAC Homer

Kraemer, A.; Doelle, A.; Schwalm, M.P.; Adhikari, Birendra Babu; Wolf, Elizabeth; Knapp, S.

doi:10.2210/pdb7q2j/pdb

Cited by 2 publications

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Rational Prediction of PROTAC-Compatible Protein–Protein Interfaces by Molecular Docking

Pereira,

Jiménez-García,

Pellarin

et al. 2023

J. Chem. Inf. Model.

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Proteolysis targeting chimeras (PROTACs) are heterobifunctional ligands that mediate the interaction between a protein target and an E3 ligase, resulting in a ternary complex, whose interaction with the ubiquitination machinery leads to target degradation. This technology is emerging as an exciting new avenue for therapeutic development, with several PROTACs currently undergoing clinical trials targeting cancer. Here, we describe a general and computationally efficient methodology combining restraint-based docking, energy-based rescoring, and a filter based on the minimal solvent-accessible surface distance to produce PROTAC-compatible PPIs suitable for when there is no a priori known PROTAC ligand. In a benchmark employing a manually curated data set of 13 ternary complex crystals, we achieved an accuracy of 92% when starting from bound structures and 77% when starting from unbound structures, respectively. Our method only requires that the ligand-bound structures of the monomeric forms of the 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 drug design campaigns where no structural information about the ternary complex structure is available.

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Rational Prediction of PROTAC-Compatible Protein–Protein Interfaces by Molecular Docking

Pereira,

Jiménez-García,

Pellarin

et al. 2023

J. Chem. Inf. Model.

View full text Add to dashboard Cite

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Rational Prediction of PROTAC-compatible Protein-Protein Interfaces by Molecular Docking

Pereira

Jiménez‐García²,

Pellarin

et al. 2023

Preprint

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Proteolysis targeting chimeras (PROTACS) are ligands that can mediate interaction between a protein target and a E3 ligase, forming a ternary complex bound to the ubiquitination machinery, leading to target degradation. This technology has become an exciting new avenue for therapeutic development, with currently two PROTACS in clinical trials targeting cancer. Nonetheless, several PROTAC drug discovery campaigns still rely on serendipity. Here, we describe a general and efficient protocol which combines restraint-based LightDock, energy-based rescoring and minimal solvent-accessible surface distance filtering to produce PROTAC-compatible PPIs. Benchmarking our protocol using a manually curated dataset of 16 ternary complex crystals, accuracies of 94% and 70% were achieved on the redocking and realistic docking experiments starting from unbound protein structures, respectively, evaluated using the CAPRI standards and DockQ. Our protocol is both accurate and computationally efficient, with potential to accelerate PROTAC drug design campaigns, particularly when the ternary complex or PROTAC are unknown.

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Quaternary Complex of human WDR5 and pVHL:ElonginC:ElonginB bound to PROTAC Homer

Cited by 2 publications

References 0 publications

Rational Prediction of PROTAC-Compatible Protein–Protein Interfaces by Molecular Docking

Rational Prediction of PROTAC-Compatible Protein–Protein Interfaces by Molecular Docking

Rational Prediction of PROTAC-compatible Protein-Protein Interfaces by Molecular Docking

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