DOCKTHOR: ANALYSIS OF PROTEIN-LIGAND DOCKING PERFORMANCE
USING THE CURATED TEST SET IRIDIUM-HT
Vizani, L. A.1; Guedes, I. A.1; Marinho, D.1, De Magalhães, C.S.2 and Dardenne, L.
E.1
Grupo de Modelagem Molecular de Sistemas Biológicos, LNCC, RJ, Brazil
1
Laboratório Nacional de Computação Científica – LNCC/MCTI
2
Universidade Federal do Rio de Janeiro – Campus Xerém - UFRJ
Protein-ligand docking methodology is an important tool in the structure-based
rational drug design. DockThor is a grid based docking program, developed by our
research group, developed to deal with highly flexible ligands using a multiplesolution steady state genetic algorithm and a scoring function based on the
MMFF94 force field. In this work, the DockThor performance was evaluated by
redocking experiments using a test set of 120 protein-ligand complexes (IridiumHT, OpenEye Scientific) comprising a wide range of different protein families and
ligands. Despite the careful filters employed to select the most reliable proteinligand complexes from the Protein Data Bank, we observed that during the
construction of Iridium-HT dataset the protonation and tautomeric states were not
correctly taken into account . We curated the dataset with PROPKA and Epik tools
to predict the correct protonation states of both protein and ligand. For each
complex the program was executed using the best DockThor docking protocol.
Top-energy conformation obtained for each complex was compared with its
experimental conformation. Furthermore, the alternative poses with similar energy
values to the top-ranked pose (difference less than or equals to 1.0 kcal/mol) were
also considered since DockThor aims to predict multiple binding modes. RMSD
values lower than or equals to 1.0Å, 2.0Å and 2.5Å from the experimental
structure were considered as success criterions. DockThor obtained very
satisfactory results in the redocking experiments considering RMSD values of
1.0Å, 2.0Å and 2.5Å as success criterion: (i) original Iridium-HT protonation states
(top-energy pose): 50%, 65.83% and 67.50%; (ii) curated structures with
PROPKA and Epik (top-energy pose): 57.5%, 78.33% and 83.33%; (iii) curated
structures prepared with PROPKA and Epik and considering solutions with similar
energies: 61.66%, 87.49% and 88.32%. It is important to note that the correct
preparation of the structures has a critical role in the success rates of docking
experiments.
Keywords: Docking, Molecular Modeling, Dockthor.
Supported by: FAPERJ, CNPq and CAPES