A hierarchical docking method, XDZ_2
OMEGA 2.5/SHAFTS/MGLTools/AutoDock Vina 1.0/ITScore_v1
Gasteiger charges #Vina
All the released crystal structures of human FXR
protein-small molecule complexes were collected from the Protein Data Bank.
If there exist more than one PDB entries containing identical small molecules
binding to the same pocket, the structure with a higher resolution was kept,
resulting in a total of 26 resulting crystal structures.
Ligand conformational libraries were generated using OMEGA.
The most stable conformation found for each ligand was then used as a starting
point for docking. Preparation for docking with Vina was done using MGLTools,
in which the ligand PDB files generated with OMEGA were converted to the PDBQT
format by assigning partial charges and atom types.
Exhaustiveness=30 #exhaustiveness of global search (default=8)
Vina scoring function (empirical + knowledge-based function)
Num_modes=500 #max number of poses to generate
Re-scoring function, ITscore_v1 #ITScore version 1.0
For a query compound, the SHAFTS program was employed to calculate
its structural similarities (i.e., the shape-feature similarities) with the small molecules
in the released FXR structures. If HybridScore > 1.2, the protein structure in the PDB entry
that has the best similarity score with the query ligand was used for docking. Otherwise,
ensemble docking was performed using all the 26 FXR protein structures collected from the PDB.
Then, a modified version of AutoDock Vina was used for the sampling, outputting up to 500 binding
models for further evaluation. A knowledge-based scoring function, ITScore_v1, was used to
evaluate these binding models. The scoring function was developed with a statistical
mechanics-based iterative method using a database containing 786 protein-ligand complex structures.