Virtual Screening Protocol on BlueGene (IGF-IR system)

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 structures Or the structures can be obtained from homology modeling or molecular dynamic simulations. 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. Finally, all the protein structures are aligned to a common frame (added hydrogen and minimize the H).

3. Database Preparation

4. Run Docking on Bluegene

(1) Make the grid for the protein.

cat <<EOF >box.in

yes

$box_margin

./selected_spheres.sph

1

box.pdb

EOF

cat <<EOF >grid.in

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

EOF

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

(2) Dock to the subset of the database