A template-based method, XDZ_0
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.
AM1-bcc #atomic charges for ligands
AMBER03 force field
Generalized Amber force field (GAFF)
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. HybridScore was used to rank the
PDB entries. If HybridScore < 1.2, only ShapeScore was used to rank the PDB entries.
Top 5 PDB entries that have the best similarity socres with the query ligand were used as
the templates. Then, the query compound was superimposed onto the ligand in each template.
For each template, the protein-query compound complex was used as the initial structure for the next
MD refinement with AMBER11. Atomic partial charges of each ligand were assigned using
Antechamber based on the AM1-bcc method after ligand minimization. Using the Leap module,
the AMBER03 force field and the Generalized Amber force field (GAFF) were applied to the
receptor and to the ligand, respectively. The hydrogen atoms, water molecules and counter
ions were also added to the complexes. The solvated complexes were then minimized in two steps.
During the first step, the solvent molecules were minimized for 1000 steps via steepest descent,
followed by 3000 steps via conjugate gradient. A 500 kcal/mol/Å^2 restraint was imposed on all
the protein atoms and ligand atoms. During the second step, the protein-ligand complexes and the
solvent were both minimized for 10,000 steps via the steepest descent method, followed by conjugate
gradient minimization until the energy gradient of the system converged to 0.01 kcal/mol/Å.