2020 Denovo tutorial 1 with PDBID 3VJK

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In a previous tutorial, we conducted virtual screenings of molecules from a small library. This means that we were identifying previously made compounds that can potentially bind the receptor. In this De Novo design, fragments of molecules are used to generate novel compounds. This can be beneficial for discovering new lead compounds--however-- there are two major drawbacks. First, it can be computationally expensive to do De Novo design. The second drawback is that the compound that is generated from using a De Novo method may not be possible to synthesize.

I. Focused De Novo

Rather than generating a large fragment library. We will be generating fragments of our original ligand.

Fragment library Generation

The first step is to make a new directory for the fragment library.

  mkdir 015.fraglib 

Next, we will make an input file for dock

  vim fraglib.in

It will contain the following:

 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                                yes
 use_internal_energy                                          yes
 internal_energy_rep_exp                                      12
 internal_energy_cutoff                                       100.0
 ligand_atom_file                                             ./../001.build/3VJK_ligand_hydrogens.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                                           ./../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

Now you will be able to run dock

  dock6 -i fraglib.in 

You should have generated the following files:

  fraglib_linker.mol2  fraglib_rigid.mol2  fraglib_scaffold.mol2  fraglib_sidechain.mol2  fraglib_torenv.dat  output_scored.mol2

These fragments should match up with the ligand that was used to generate the library.

Focus Denovo

We will be now conducting focus denovo.

mkdir 017.focused_denovo/

cd 017.focused_denovo/

vi focus.in

   conformer_search_type                                        denovo
   dn_fraglib_scaffold_file                                     ./../015.fraglib/fraglib_scaffold.mol2
   dn_fraglib_linker_file                                       ./../015.fraglib/fraglib_linker.mol2
   dn_fraglib_sidechain_file                                    ./../015.fraglib/fraglib_sidechain.mol2
   dn_user_specified_anchor                                     no
  dn_use_torenv_table                                          yes
  dn_torenv_table                                              ./../015.fraglib/fraglib_torenv.dat
  dn_sampling_method                                           graph
  dn_graph_max_picks                                           30
  dn_graph_breadth                                             3
  dn_graph_depth                                               2
  dn_graph_temperature                                         100.0
  dn_pruning_conformer_score_cutoff                            100.0
  dn_pruning_conformer_score_scaling_factor                    1.0
 dn_pruning_clustering_cutoff                                 100.0
 dn_constraint_mol_wt                                         550
 dn_constraint_rot_bon                                        15
  dn_constraint_formal_charge                                  2
  dn_heur_unmatched_num                                        1
  dn_heur_matched_rmsd                                         2
  dn_unique_anchors                                            1
 dn_max_grow_layers                                           9
 dn_max_root_size                                             5
  dn_max_layer_size                                            25
  dn_max_current_aps                                           5
  dn_max_scaffolds_per_layer                                   1
 dn_write_checkpoints                                         yes
 dn_write_prune_dump                                          no
 dn_write_orients                                             no
  dn_write_growth_trees                                        yes
 dn_output_prefix                                             3vjk.final
 use_internal_energy                                          yes
 internal_energy_rep_exp                                      12
  internal_energy_cutoff                                       100.0
  use_database_filter                                          no
  orient_ligand                                                yes
  automated_matching                                           yes
  receptor_site_file                                           ./../002.surface_spheres/selected_spheres.sph
  max_orientations                                             1000
  critical_points                                              no
  chemical_matching                                            no
  use_ligand_spheres                                           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                                       ./../003.gridbox/grid
 multigrid_score_secondary                                    no
 dock3.5_score_secondary                                      no
 continuous_score_secondary                                   no
 footprint_similarity_score_secondary                         no
 pharmacophore_score_secondary                                no
 descriptor_score_secondary                                   no
 gbsa_zou_score_secondary                                     no
 gbsa_hawkins_score_secondary                                 no
 SASA_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                                       .1
 simplex_cycle_converge                                       1
 simplex_trans_step                                           1
 simplex_rot_step                                             .1
 simplex_tors_step                                            10
 simplex_anchor_max_iterations                                500
 simplex_grow_max_iterations                                  500
 simplex_grow_tors_premin_iterations                          0
 simplex_random_seed                                          0
 simplex_restraint_min                                        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

vi rescore.in

  conformer_search_type                                        flex
   write_fragment_libraries                                     no
   user_specified_anchor                                        no
   limit_max_anchors                                            no
   min_anchor_size                                              5
   pruning_use_clustering                                       yes
   pruning_max_orients                                          1000
   pruning_clustering_cutoff                                    100
   pruning_conformer_score_cutoff                               100.0
   pruning_conformer_score_scaling_factor                       1.0
  use_clash_overlap                                            no
  write_growth_tree                                            no
  use_internal_energy                                          yes
  internal_energy_rep_exp                                      12
  internal_energy_cutoff                                       100.0
  ligand_atom_file                                             ./../016.denovo/3vjk.final.denovo_build.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                                           ./../002.surface_spheres/selected_spheres.sph
  max_orientations                                             1000
  critical_points                                              no
  chemical_matching                                            no 
   use_ligand_spheres                                           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                                       ./../003.gridbox/grid
  multigrid_score_secondary                                    no
  dock3.5_score_secondary                                      no
  continuous_score_secondary                                   no
  footprint_similarity_score_secondary                         no
  pharmacophore_score_secondary                                no
  descriptor_score_secondary                                   no
  gbsa_zou_score_secondary                                     no
  gbsa_hawkins_score_secondary                                 no
  SASA_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
  simplex_restraint_min                                        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