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Blinded evaluation of cathepsin S inhibitors from the D3RGC3 dataset using molecular docking and free energy calculations

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Abstract

During the last few years, we have developed a docking protocol involving two steps: (i) the choice of the most appropriate docking software and parameters for the system of interest using structural and functional information available in public databases (PDB, ChEMBL, PubChem Assay, BindingDB, etc.); (ii) the docking of ligand dataset to provide a prediction for the binding modes and ranking of ligands. We applied this protocol to the D3R Grand Challenge 3 dataset containing cathepsin S (CatS) inhibitors. Considering the size and conformational flexibility of ligands, the docking calculations afforded reasonable overall pose predictions, which are however dependent on the specific nature of each ligand. As expected, the correct ranking of docking poses is still challenging. Post-processing of docking poses with molecular dynamics simulations in explicit solvent provided a significantly better prediction, whereas free energy calculations on a subset of compounds brought no significant improvement in the ranking prediction compared with the direct ranking obtained from the scoring function.

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Acknowledgements

We thank Prof. Bert de Groot for helpful discussions. This work was supported by the Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT) (Agence Nationale de la Recherche, Grant Number ANR-10-LABX-33), by the JPIAMR transnational project DesInMBL (Agence Nationale de la Recherche, Grant Number ANR-14-JAMR-0002) and by the Région Ile-de-France (Conseil Régional, Île-de-France, DIM Malinf).

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Author notes

  1. Ludovic Chaput, Edithe Selwa and Eddy Elisée have contributed equally to this work.

Authors and Affiliations

  1. Institut de Chimie des Substances Naturelles, CNRS UPR 2301, LabEx LERMIT, 91198, Gif-sur-Yvette, France

    Ludovic Chaput, Edithe Selwa, Eddy Elisée & Bogdan I. Iorga

  2. Department of Nephrology and Dialysis, AP-HP, Tenon Hospital, INSERM UMR_S 1155, 75020, Paris, France

    Ludovic Chaput

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  1. Ludovic Chaput
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  2. Edithe Selwa
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  4. Bogdan I. Iorga
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Corresponding author

Correspondence to Bogdan I. Iorga.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10822_2018_161_MOESM1_ESM.pdf

The Electronic Supplementary Material contains the list of CatS crystal structures from the PDB, the chemical structures of the scoring CatS D3RGC3 dataset, and the plots showing the performance of our submissions.

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Chaput, L., Selwa, E., Elisée, E. et al. Blinded evaluation of cathepsin S inhibitors from the D3RGC3 dataset using molecular docking and free energy calculations. J Comput Aided Mol Des 33, 93–103 (2019). https://doi.org/10.1007/s10822-018-0161-7

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  • DOI: https://doi.org/10.1007/s10822-018-0161-7

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