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  Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset.

Elisee, E., Gapsys, V., Mele, N., Chaput, L., Selwa, E., de Groot, B. L., et al. (2019). Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset. Journal of Computer-Aided Molecular Design, 33, 1031-1043. doi:10.1007/s10822-019-00232-w.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-1E16-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-603C-C
Genre: Journal Article

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 Creators:
Elisee, E., Author
Gapsys, V.1, Author              
Mele, N., Author
Chaput, L., Author
Selwa, E., Author
de Groot, B. L.1, Author              
Iorga, B. I., Author
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578573              

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Free keywords: Molecular docking; Free energy calculations; Molecular dynamics; Pmx; D3R challenge; Beta secretase 1; Cathepsin S; Inhibitors
 Abstract: Using the D3R Grand Challenge 4 dataset containing Beta-secretase 1 (BACE) and Cathepsin S (CatS) inhibitors, we have evaluated the performance of our in-house docking workflow that involves in the first step the selection of the most suitable docking software for the system of interest based on structural and functional information available in public databases, followed by the docking of the dataset to predict the binding modes and ranking of ligands. The macrocyclic nature of the BACE ligands brought additional challenges, which were dealt with by a careful preparation of the three-dimensional input structures for ligands. This provided top-performing predictions for BACE, in contrast with CatS, where the predictions in the absence of guiding constraints provided poor results. These results highlight the importance of previous structural knowledge that is needed for correct predictions on some challenging targets. After the end of the challenge, we also carried out free energy calculations (i.e. in a non-blinded manner) for CatS using the pmx software and several force fields (AMBER, Charmm). Using knowledge-based starting pose construction allowed reaching remarkable accuracy for the CatS free energy estimates. Interestingly, we show that the use of a consensus result, by averaging the results from different force fields, increases the prediction accuracy.

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Language(s): eng - English
 Dates: 2019-11-012019-12
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1007/s10822-019-00232-w
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Title: Journal of Computer-Aided Molecular Design
Source Genre: Journal
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Pages: - Volume / Issue: 33 Sequence Number: - Start / End Page: 1031 - 1043 Identifier: -