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Ligand- and receptor-based docking with LiBELa

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Abstract

Methodologies on molecular docking are constantly improving. The problem consists on finding an optimal interplay between the computational cost and a satisfactory physical description of ligand-receptor interaction. In pursuit of an advance in current methods we developed a mixed docking approach combining ligand- and receptor-based strategies in a docking engine, where tridimensional descriptors for shape and charge distribution of a reference ligand guide the initial placement of the docking molecule and an interaction energy-based global minimization follows. This hybrid docking was evaluated with soft-core and force field potentials taking into account ligand pose and scoring. Our approach was found to be competitive to a purely receptor-based dock resulting in improved logAUC values when evaluated with DUD and DUD-E. Furthermore, the smoothed potential as evaluated here, was not advantageous when ligand binding poses were compared to experimentally determined conformations. In conclusion we show that a combination of ligand- and receptor-based strategy docking with a force field energy model results in good reproduction of binding poses and enrichment of active molecules against decoys. This strategy is implemented in our tool, LiBELa, available to the scientific community.

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Acknowledgments

The authors thank Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), and to the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for the financial support through grants 2014/06565-2 and 485950/2013-8. HSM also thanks CNPq for her PhD stipend. We also thank Dr. Paul Hawkings and João Victor Cunha for the fruitful discussions.

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Authors and Affiliations

  1. Instituto de Física de São Carlos, Av. Trabalhador são-carlense, 400. Centro, São Carlos, SP, 13566-590, Brazil

    Heloisa dos Santos Muniz & Alessandro S. Nascimento

Authors
  1. Heloisa dos Santos Muniz
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  2. Alessandro S. Nascimento
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Corresponding author

Correspondence to Alessandro S. Nascimento.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Figure 1

Individual ROC curves for DUD. The fraction of decoys is shown on horizontal axis on log scale while the vertical axis brings the fraction of actives found in the energy-ranked docking result. The results for Amber FF model (green), Amber Smoothed energy model (cyan), DOCK6 Grid Score (black), Ligand-Based Similarity (blue) are compared in the same plot with what would be expected at random (red line) (TIFF 1157 kb)

Supplementary Figure 2

Continuing Supplementary Figure 1 (TIFF 3895 kb)

Supplementary Figure 3

Individual ROC curves for DUD-E. The fraction of decoys is shown on horizontal axis on log scale while the vertical axis brings the fraction of actives found in the energy-ranked docking result. The results for Amber FF model (green), Amber Smoothed energy model (cyan), DOCK6 Grid Score (black), Ligand-Based Similarity (blue) are compared in the same plot with what would be expected at random (red line) (TIFF 3602 kb)

Spreadsheet with individual RMSD values for each target in SB2012 self-docking experiment (ODS 261 kb)

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dos Santos Muniz, H., Nascimento, A.S. Ligand- and receptor-based docking with LiBELa. J Comput Aided Mol Des 29, 713–723 (2015). https://doi.org/10.1007/s10822-015-9856-1

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  • DOI: https://doi.org/10.1007/s10822-015-9856-1

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