Revision as of 10:35, 10 March 2020

I. Focused De Novo Design with PDB 4F4P

This tutorial assumes that you have finished the virtual screening of this system ([1]). We are going to used some of the files generated by the VS toturial.

Fragment Librarie

A focused fragment library will be used in this tutorial, in order to attempt building the same ligand. A focused fragment library can be generated using the same ligand.

Create a new directory for the fragment library.

mkdir fraglib

Inside the fraglib directory create a new input file for fragment generation.

vi fraglib.in

Generate the fragments by calling the input file through DOCK6

dock6 -i fraglib.in -o fradlib.out

Answer the prompted questions interactively using the following lines.

conformer_search_type                                        flex
write_fragment_libraries                                     yes
fragment_library_prefix                                      fraglib
fragment_library_freq_cutoff                                 1
fragment_library_sort_method                                 freq
fragment_library_trans_origin                                no
use_internal_energy                                          yes
internal_energy_rep_exp                                      9
internal_energy_cutoff                                       100.0
ligand_atom_file                                             (your path for VS docking)/001.files/4f4p_lig_h.mol2
limit_max_ligands                                            no
skip_molecule                                                no
read_mol_solvation                                           no
calculate_rmsd                                               no
use_database_filter                                          no
orient_ligand                                                yes
automated_matching                                           yes
receptor_site_file                                           (your path for VS docking)/002.surface_spheres/selected_spheres.sph
max_orientations                                             1000
critical_points                                              no
chemical_matching                                            no
use_ligand_spheres                                           no
bump_filter                                                  no
score_molecules                                              no
atom_model                                                   all
vdw_defn_file                                                /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/vdw_AMBER_parm99.defn
flex_defn_file                                               /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/flex.defn
flex_drive_file                                              /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/flex_drive.tbl
ligand_outfile_prefix                                        output
write_orientations                                           no
num_scored_conformers                                        1
rank_ligands                                                 no

Once fragment generation is completed, following files will be generated. (fraglib_linker.mol2, fraglib_rigid.mol2, fraglib_scaffold.mol2, fraglib_sidechain.mol2, fraglib_torenv.dat) You can use the following commands to check the number of fragments in each file.

grep -wc MOLECULE *.mol2

You can also open the mol2 files using chimera and check if the fragments match with the ligand used for fragment generation.