Virtual Screening Protocol on BlueGene (IGF-IR system)

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For this document, virtual screening protocol will be described in detail for IGF-IR system (by Yulin Huang).

1. Identify the target

This is the very fist step for virtual screening. Usually, a single or multiple proteins are selected as targets if their mutations or overexpression are implicated in certain diseases. However, disease relevance alone is not sufficient for target identification. Moreover, the target must be druggable which means the target should be predicted to bind to a drug with high affinity and this binding will bring therapeutic benefit to the patients. The target is defined as druggable if there are drugs already identified for it. Otherwise, druggability can be predicted using evolution rules, structural properties or other destructors.

2. Prepare the target

At this step, you need to prepare the protein structure used for virtual screening. The structures can be downloaded from PDB database if they are available. Make sure which form of the structure should be used. For example, for IGF-IR system, PDB structures have been released for active, inactive, and intermediate forms. Or the structures can be obtained from homology modeling or molecular dynamic simulations. All the protein structures are aligned to a common frame and processed with AMBER tleap program. Hydrogen was added and minimized and force field parameters were assigned. Monoatomic ions should be carefully treated and usually they are treated as part of the receptor if they were within ca. 10Å from the binding site. In terms of water molecules, prior knowledge is needed for decisions. If the system is known to have water-mediated interactions (i.e, ErbB family receptors), then the waters should be included as part of the receptors. If not, waters should be removed. For histidine residues, they are treated based on the environment, i.e., which nitrogen was coordinated with ions and/or ligands.

3. Database Preparation

4. Run Docking on Bluegene

(1) Make the grid for the protein. For IGF-IR system, active (PDB 2ZM3), inactive (PDB 3NW5) and intermediate forms(PDB 3D94)are used. For this document, only results for 3D94 are reported.

cat <<EOF >


cat <<EOF >

compute_grids                                                yes
grid_spacing                                                 $grid_spacing
output_molecule                                              yes
contact_score                                                no
chemical_score                                               no
energy_score                                                 yes
energy_cutoff_distance                                       999
atom_model                                                   a
attractive_exponent                                          ${attractive}
repulsive_exponent                                           ${repulsive}
distance_dielectric                                          yes
dielectric_factor                                            4
bump_filter                                                  yes
bump_overlap                                                 0.75
receptor_file                                                ./receptor.mol2
box_file                                                     ./box.pdb
vdw_definition_file                                          ./vdw.defn
chemical_definition_file                                     ./chem.defn
score_grid_prefix                                            ./${system}.rec
receptor_out_file                                            ./${system}.rec.grid.mol2


Among them, the parameters are set as follows: set grid_spacing = 0.3 set attractive = 6 set repulsive = 9 set box_margin = 8

(2) Dock to the subset of the database

ligand_atom_file                                             ${ligfile}
limit_max_ligands                                            no
skip_molecule                                                no
read_mol_solvation                                           no
calculate_rmsd                                               no
use_database_filter                                          yes
dbfilter_max_heavy_atoms                                     1000
dbfilter_min_heavy_atoms                                     0
dbfilter_max_rot_bonds                                       15
dbfilter_min_rot_bonds                                       0
dbfilter_max_molwt                                           10000
dbfilter_min_molwt                                           0
dbfilter_max_formal_charge                                   2
dbfilter_min_formal_charge                                   -2
dbfilter_max_xlogp                                           20
dbfilter_min_xlogp                                           -20
orient_ligand                                                yes
automated_matching                                           yes
receptor_site_file                                           ${sphfile}
max_orientations                                             1000
critical_points                                              no
chemical_matching                                            no
use_ligand_spheres                                           no
use_internal_energy                                          yes
internal_energy_rep_exp                                      12
flexible_ligand                                              yes
min_anchor_size                                              5
pruning_use_clustering                                       yes
pruning_max_orients                                          1000
pruning_clustering_cutoff                                    100
pruning_conformer_score_cutoff                               100
use_clash_overlap                                            no
print_growth_tree                                            no
bump_filter                                                  no
score_molecules                                              yes
contact_score_primary                                        no
contact_score_secondary                                      no
grid_score_primary                                           yes
grid_score_secondary                                         no
grid_score_rep_rad_scale                                     1
grid_score_vdw_scale                                         1
grid_score_es_scale                                          1
grid_score_grid_prefix                                       ${gridprefix}
dock3.5_score_secondary                                      no
continuous_score_secondary                                   no
descriptor_score_secondary                                   no
gbsa_zou_score_secondary                                     no
gbsa_hawkins_score_secondary                                 no
amber_score_secondary                                        no
minimize_ligand                                              yes
minimize_anchor                                              yes
minimize_flexible_growth                                     yes
use_advanced_simplex_parameters                              no
simplex_max_cycles                                           1
simplex_score_converge                                       0.1
simplex_cycle_converge                                       1.0
simplex_trans_step                                           1.0
simplex_rot_step                                             0.1
simplex_tors_step                                            10.0
simplex_anchor_max_iterations                                500
simplex_grow_max_iterations                                  500
simplex_grow_tors_premin_iterations                          0
simplex_random_seed                                          0
restraint_min                                                no
atom_model                                                   all
vdw_defn_file                                                $defn_dir/vdw_AMBER_parm99.defn
flex_defn_file                                               $defn_dir/flex.defn
flex_drive_file                                              $defn_dir/flex_drive.tbl
ligand_outfile_prefix                                                                           ${system}.${vendor}.${chunk}.100.flx.${protocol}.dock2grid
write_orientations                                           no
num_scored_conformers                                        1
write_conformations                                          no
rank_ligands                                                 no