Difference between revisions of "2021 Denovo tutorial 4 with PDBID 1EFY"

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−
= Introduction =
+
=Introduction=
−
This tutorial is the second in a series of DOCK tutorials. For part I, please click here. De novo design, in practice, consists of two steps: (1) fragment library generation and (2) de novo construction. DOCK directs ligand assembly in an iterative manner; structures are grown layer by layer as DOCK samples different fragments from the sidechain, linker, and scaffold libraries.
+
This tutorial is the second in a series of DOCK tutorials. For part I, please click [https://ringo.ams.stonybrook.edu/index.php/2021_DOCK_tutorial_4_with_PDBID_1EFY#Generating_Box_and_Grid here]. De novo design, in practice, consists of two steps:  
−
==Fragment library generation==
+
*(1) fragment library generation and  
−
Fragments are the basic unit of a molecule (in DOCK, that is). In general, fragments will not contain any rotatable bonds, and are treated as rigid units. The general workflow for fragment library generation proceeds in the following manner:
+
*(2) de novo construction.  
−
Break the molecule(s) in the input file at each rotatable bond and insert dummy atoms at the point of cleavage.
+
DOCK directs ligand assembly in an iterative manner; structures are grown layer by layer as DOCK samples different fragments from the sidechain, linker, and scaffold libraries.
−
Classify the resulting fragments as sidechains (which have one dummy atom), linkers (which have 2 dummy atoms), or scaffolds (which have three or more dummy atoms).
+
In this tutorial, we will be performing two rounds of de novo design: once using a fragment library generated from the original ligand that was complexed with our receptor in the crystal structure, and once with a fragment library generated from many other druglike ligands.
 +
==Fragment Library Generation==
 +
Fragments are the basic unit of a molecule in DOCK_DN. In general, fragments will not contain any rotatable bonds, and are treated as rigid units. The general workflow for fragment library generation proceeds in the following manner:
 +
*Break the molecule(s) in the input file at each rotatable bond and insert dummy atoms at the point of cleavage.
 +
*Classify the resulting fragments as sidechains (which have one dummy atom), linkers (which have 2 dummy atoms), or scaffolds (which have three or more dummy atoms).
 +
==Software Requirements==
 +
In order to successfully follow this tutorial, please make sure to have the following programs installed:
 +
*[https://mobaxterm.mobatek.net/ MobaXterm] (for Windows users)
 +
*[https://www.cgl.ucsf.edu/chimera/download.html Chimera 1.15] (Please choose the right specifications for your OS)
 +
*DOCK 6.9
 +
 
 +
We will be using a shell environment (either the built-in terminal for MacOS/Linux users or MobaXTerm for Windows users) to run several of the programs in this tutorial. As such, it may be useful to familiarize yourself with running [https://lweb.cfa.harvard.edu/rtdc/shell_cmds/basic/ basic UNIX commands] and [https://www.openvim.com/ VIM].
 +
 
 +
In addition, this tutorial assumes you have access to a High Performance Computing cluster, i.e. [https://it.stonybrook.edu/help/kb/understanding-seawulf Seawulf].
 +
 
 
==Directory Setup==
 
==Directory Setup==
 
Before we begin building our libraries, we should setup our directory structure:
 
Before we begin building our libraries, we should setup our directory structure:
−
  mkdir fraglib dn_focus dn_focus_rescore dn_generic
+
  mkdir fraglib dn_focus dn_focus_rescore dn_generic dn_generic_rescore
 +
 
 
=Focused De Novo Design=
 
=Focused De Novo Design=
 
==Fragment Libraries==
 
==Fragment Libraries==
−
In the first part of the tutorial, we will be building a library of fragments out of our original ligand, the benzimidazol inhibitor. Enter the fraglib directory
+
In the first part of the tutorial, we will be building a library of fragments out of our original ligand, the benzimidazol inhibitor. Move into the '''fraglib''' directory
 
  cd fragllib
 
  cd fragllib
−
Now create a new input file called fraglib.in. This file will be used for generating fragments.
+
Now create a new input file called '''fraglib.in'''. This file will be used for generating fragments.
 
  touch fraglib.in
 
  touch fraglib.in
 
Now interactively run the file in DOCK6:
 
Now interactively run the file in DOCK6:
Line 56: Line 71:
 
  fraglib_linker.mol2, fraglib_rigid.mol2, fraglib_scaffold.mol2, fraglib_sidechain.mol2,  
 
  fraglib_linker.mol2, fraglib_rigid.mol2, fraglib_scaffold.mol2, fraglib_sidechain.mol2,  
 
  fraglib_torenv.dat, fraglib.out_scored.mol2
 
  fraglib_torenv.dat, fraglib.out_scored.mol2
 +
 +
==Focused De Novo Growth==
 +
Next we will be performing the second step of the de novo process: growth.
 +
Move into the '''dn_focus''' directory.
 +
cd dn_focus
 +
Create an input file for DOCK:
 +
touch focus.in
 +
Run DOCK interactively:
 +
dock6 -i focus.in -o dn_focus.out
 +
conformer_search_type                                        denovo
 +
dn_fraglib_scaffold_file                                    ../fraglib/fraglib_scaffold.mol2
 +
dn_fraglib_linker_file                                      ../fraglib/fraglib_linker.mol2
 +
dn_fraglib_sidechain_file                                    ../fraglib/fraglib_sidechain.mol2
 +
dn_user_specified_anchor                                    no
 +
dn_use_torenv_table                                          yes
 +
dn_torenv_table                                              ../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                                        550.0
 +
dn_constraint_rot_bon                                        15
 +
dn_constraint_formal_charge                                  2.0
 +
dn_heur_unmatched_num                                        1
 +
dn_heur_matched_rmsd                                        2.0
 +
dn_unique_anchors                                            1
 +
dn_max_grow_layers                                          9
 +
dn_max_root_size                                            25
 +
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                                        no
 +
dn_output_prefix                                            dn_focus.out
 +
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                                          ../fraglib/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                                      ../../../1EFY/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
 +
 +
==Focused Denovo Rescore==
 +
Move into the '''dn_focus_rescore''' directory:
 +
cd dn_focus_rescore
 +
Create the following input file:
 +
touch dn_rescore.in
 +
Run the input file through DOCK interactively:
 +
dock6 -i dn_rescore.in
 +
 +
conformer_search_type                                        rigid
 +
use_internal_energy                                          yes
 +
internal_energy_rep_exp                                      12
 +
internal_energy_cutoff                                      100.0
 +
ligand_atom_file                                            ../dn_focus/dn_focus.out.denovo_build.mol2
 +
limit_max_ligands                                            no
 +
skip_molecule                                                no
 +
read_mol_solvation                                          no
 +
calculate_rmsd                                              no
 +
use_database_filter                                          no
 +
orient_ligand                                                no
 +
bump_filter                                                  no
 +
score_molecules                                              yes
 +
contact_score_primary                                        no
 +
contact_score_secondary                                      no
 +
grid_score_primary                                          no
 +
grid_score_secondary                                        no
 +
multigrid_score_primary                                      no
 +
multigrid_score_secondary                                    no
 +
dock3.5_score_primary                                        no
 +
dock3.5_score_secondary                                      no
 +
continuous_score_primary                                    no
 +
continuous_score_secondary                                  no
 +
footprint_similarity_score_primary                          no
 +
footprint_similarity_score_secondary                        no
 +
pharmacophore_score_primary                                  no
 +
pharmacophore_score_secondary                                no
 +
descriptor_score_primary                                    yes
 +
descriptor_score_secondary                                  no
 +
descriptor_use_grid_score                                    no
 +
descriptor_use_multigrid_score                              no
 +
descriptor_use_continuous_score                              no
 +
descriptor_use_footprint_similarity                          yes
 +
descriptor_use_pharmacophore_score                          yes
 +
descriptor_use_tanimoto                                      yes
 +
descriptor_use_hungarian                                    yes
 +
descriptor_use_volume_overlap                                yes
 +
descriptor_fps_score_use_footprint_reference_mol2            yes
 +
descriptor_fps_score_footprint_reference_mol2_filename      ../fraglib/1EFY.lig.min_scored.mol2
 +
descriptor_fps_score_foot_compare_type                      Euclidean
 +
descriptor_fps_score_normalize_foot                          no
 +
descriptor_fps_score_foot_comp_all_residue                  yes
 +
descriptor_fps_score_receptor_filename                      ../fraglib/1EFY_rec_dockprep.mol2
 +
descriptor_fps_score_vdw_att_exp                            6
 +
descriptor_fps_score_vdw_rep_exp                            12
 +
descriptor_fps_score_vdw_rep_rad_scale                      1
 +
descriptor_fps_score_use_distance_dependent_dielectric      yes
 +
descriptor_fps_score_dielectric                              4.0
 +
descriptor_fps_score_vdw_fp_scale                            1
 +
descriptor_fps_score_es_fp_scale                            1
 +
descriptor_fps_score_hb_fp_scale                            0
 +
descriptor_fms_score_use_ref_mol2                            yes
 +
descriptor_fms_score_ref_mol2_filename                      ../fraglib/1EFY.lig.min_scored.mol2
 +
descriptor_fms_score_write_reference_pharmacophore_mol2      no
 +
descriptor_fms_score_write_reference_pharmacophore_txt      no
 +
descriptor_fms_score_write_candidate_pharmacophore          no
 +
descriptor_fms_score_write_matched_pharmacophore            no
 +
descriptor_fms_score_compare_type                            overlap
 +
descriptor_fms_score_full_match                              yes
 +
descriptor_fms_score_match_rate_weight                      5.0
 +
descriptor_fms_score_match_dist_cutoff                      1.0
 +
descriptor_fms_score_match_proj_cutoff                      0.7071
 +
descriptor_fms_score_max_score                              20
 +
descriptor_fingerprint_ref_filename                          ../fraglib/1EFY.lig.min_scored.mol2
 +
descriptor_hms_score_ref_filename                            ../fraglib/1EFY.lig.min_scored.mol2
 +
descriptor_hms_score_matching_coeff                          -5
 +
descriptor_hms_score_rmsd_coeff                              1
 +
descriptor_volume_score_reference_mol2_filename              ../fraglib/1EFY.lig.min_scored.mol2
 +
descriptor_volume_score_overlap_compute_method              analytical
 +
descriptor_weight_fps_score                                  1
 +
descriptor_weight_pharmacophore_score                        1
 +
descriptor_weight_fingerprint_tanimoto                      -1
 +
descriptor_weight_hms_score                                  1
 +
descriptor_weight_volume_overlap_score                      -1
 +
gbsa_zou_score_secondary                                    no
 +
gbsa_hawkins_score_secondary                                no
 +
SASA_score_secondary                                        no
 +
amber_score_secondary                                        no
 +
minimize_ligand                                              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
 +
chem_defn_file                                             
 +
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/chem.defn
 +
pharmacophore_defn_file                                     
 +
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/ph4.defn
 +
ligand_outfile_prefix                                        descriptor.output
 +
write_footprints                                            yes
 +
write_hbonds                                                yes
 +
write_orientations                                          no
 +
num_scored_conformers                                        1
 +
rank_ligands                                                no
 +
The following files should have been generated:
 +
descriptor.output_footprint_scored.txt, descriptor.output_hbond_scored.txt, descriptor.output_scored.txt
 +
 +
=Generic Denovo Growth=
 +
==Generic Fragment Library==
 +
Move into the '''dn_generic_denovo''' directory:
 +
cd dn_generic_denovo
 +
Create the following input file:
 +
touch gn_denovo.in
 +
Run the input file interactively in DOCK:
 +
dock6 -i gn_denovo.in -o gn_denovo.out
 +
 +
conformer_search_type                                        denovo
 +
dn_fraglib_scaffold_file                                   
 +
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/fraglib_scaffold.mol2
 +
dn_fraglib_linker_file                                     
 +
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/fraglib_linker.mol2
 +
dn_fraglib_sidechain_file                                   
 +
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/fraglib_sidechain.mol2
 +
dn_user_specified_anchor                                    no
 +
dn_use_torenv_table                                          yes
 +
dn_torenv_table                                             
 +
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/fraglib_torenv.dat
 +
dn_sampling_method                                          graph
 +
dn_graph_max_picks                                          30
 +
dn_graph_breadth                                            3
 +
dn_graph_depth                                              2
 +
dn_graph_temperature                                        100
 +
dn_pruning_conformer_score_cutoff                            100
 +
dn_pruning_conformer_score_scaling_factor                    1.0
 +
dn_pruning_clustering_cutoff                                100.0
 +
dn_constraint_mol_wt                                        550.0
 +
dn_constraint_rot_bon                                        15
 +
dn_constraint_formal_charge                                  2.0
 +
dn_heur_unmatched_num                                        1
 +
dn_heur_matched_rmsd                                        2.0
 +
dn_unique_anchors                                            1
 +
dn_max_grow_layers                                          9
 +
dn_max_root_size                                            25
 +
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                                        no
 +
dn_output_prefix                                            gn_denovo_output
 +
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                                          ../fraglib/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                                          no
 +
grid_score_secondary                                        no
 +
multigrid_score_primary                                      no
 +
multigrid_score_secondary                                    no
 +
dock3.5_score_primary                                        no
 +
dock3.5_score_secondary                                      no
 +
continuous_score_primary                                    no
 +
continuous_score_secondary                                  no
 +
footprint_similarity_score_primary                          no
 +
footprint_similarity_score_secondary                        no
 +
pharmacophore_score_primary                                  no
 +
pharmacophore_score_secondary                                no
 +
descriptor_score_primary                                    yes
 +
descriptor_score_secondary                                  no
 +
descriptor_use_grid_score                                    yes
 +
descriptor_use_pharmacophore_score                          no
 +
descriptor_use_tanimoto                                      no
 +
descriptor_use_hungarian                                    no
 +
descriptor_use_volume_overlap                                no
 +
descriptor_grid_score_rep_rad_scale                          1
 +
descriptor_grid_score_vdw_scale                              1
 +
descriptor_grid_score_es_scale                              1
 +
descriptor_grid_score_grid_prefix                            ../../../1EFY/003.gridbox/grid
 +
descriptor_weight_grid_score                                1
 +
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
 +
==Generic Denovo Rescore==
 +
Move into the '''dn_generic_rescore''' directory
 +
cd dn_generic_rescore
 +
Create the following input file:
 +
touch gn_rescore.in
 +
Run the input file interactively in DOCK:
 +
dock6 -i gn_rescore.in -o gn_resocre.out
 +
 +
conformer_search_type                                        rigid
 +
use_internal_energy                                          yes
 +
internal_energy_rep_exp                                      12
 +
internal_energy_cutoff                                      100.0
 +
ligand_atom_file                                            ../11_dn_focus/dn_generic.out.denovo_build.mol2
 +
limit_max_ligands                                            no
 +
skip_molecule                                                no
 +
read_mol_solvation                                          no
 +
calculate_rmsd                                              no
 +
use_database_filter                                          no
 +
orient_ligand                                                no
 +
bump_filter                                                  no
 +
score_molecules                                              yes
 +
contact_score_primary                                        no
 +
contact_score_secondary                                      no
 +
grid_score_primary                                          no
 +
grid_score_secondary                                        no
 +
multigrid_score_primary                                      no
 +
multigrid_score_secondary                                    no
 +
dock3.5_score_primary                                        no
 +
dock3.5_score_secondary                                      no
 +
continuous_score_primary                                    no
 +
continuous_score_secondary                                  no
 +
footprint_similarity_score_primary                          no
 +
footprint_similarity_score_secondary                        no
 +
pharmacophore_score_primary                                  no
 +
pharmacophore_score_secondary                                no
 +
descriptor_score_primary                                    yes
 +
descriptor_score_secondary                                  no
 +
descriptor_use_grid_score                                    no
 +
descriptor_use_multigrid_score                              no
 +
descriptor_use_continuous_score                              no
 +
descriptor_use_footprint_similarity                          yes
 +
descriptor_use_pharmacophore_score                          yes
 +
descriptor_use_tanimoto                                      yes
 +
descriptor_use_hungarian                                    yes
 +
descriptor_use_volume_overlap                                yes
 +
descriptor_fps_score_use_footprint_reference_mol2            yes
 +
descriptor_fps_score_footprint_reference_mol2_filename      ../fraglib/1EFY.lig.min_scored.mol2
 +
descriptor_fps_score_foot_compare_type                      Euclidean
 +
descriptor_fps_score_normalize_foot                          no
 +
descriptor_fps_score_foot_comp_all_residue                  yes
 +
descriptor_fps_score_receptor_filename                      ../fraglib/1EFY_rec_dockprep.mol2
 +
descriptor_fps_score_vdw_att_exp                            6
 +
descriptor_fps_score_vdw_rep_exp                            12
 +
descriptor_fps_score_vdw_rep_rad_scale                      1
 +
descriptor_fps_score_use_distance_dependent_dielectric      yes
 +
descriptor_fps_score_dielectric                              4.0
 +
descriptor_fps_score_vdw_fp_scale                            1
 +
descriptor_fps_score_es_fp_scale                            1
 +
descriptor_fps_score_hb_fp_scale                            0
 +
descriptor_fms_score_use_ref_mol2                            yes
 +
descriptor_fms_score_ref_mol2_filename                      ../fraglib/1EFY.lig.min_scored.mol2
 +
descriptor_fms_score_write_reference_pharmacophore_mol2      no
 +
descriptor_fms_score_write_reference_pharmacophore_txt      no
 +
descriptor_fms_score_write_candidate_pharmacophore          no
 +
descriptor_fms_score_write_matched_pharmacophore            no
 +
descriptor_fms_score_compare_type                            overlap
 +
descriptor_fms_score_full_match                              yes
 +
descriptor_fms_score_match_rate_weight                      5.0
 +
descriptor_fms_score_match_dist_cutoff                      1.0
 +
descriptor_fms_score_match_proj_cutoff                      0.7071
 +
descriptor_fms_score_max_score                              20
 +
descriptor_fingerprint_ref_filename                          ../fraglib/1EFY.lig.min_scored.mol2
 +
descriptor_hms_score_ref_filename                            ../fraglib/1EFY.lig.min_scored.mol2
 +
descriptor_hms_score_matching_coeff                          -5
 +
descriptor_hms_score_rmsd_coeff                              1
 +
descriptor_volume_score_reference_mol2_filename              ../fraglib/1EFY.lig.min_scored.mol2
 +
descriptor_volume_score_overlap_compute_method              analytical
 +
descriptor_weight_fps_score                                  1
 +
descriptor_weight_pharmacophore_score                        1
 +
descriptor_weight_fingerprint_tanimoto                      -1
 +
descriptor_weight_hms_score                                  1
 +
descriptor_weight_volume_overlap_score                      -1
 +
gbsa_zou_score_secondary                                    no
 +
gbsa_hawkins_score_secondary                                no
 +
SASA_score_secondary                                        no
 +
amber_score_secondary                                        no
 +
minimize_ligand                                              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
 +
chem_defn_file                                              /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/chem.defn
 +
pharmacophore_defn_file                                      /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/ph4.defn
 +
ligand_outfile_prefix                                        descriptor.output
 +
write_footprints                                            yes
 +
write_hbonds                                                yes
 +
write_orientations                                          no
 +
num_scored_conformers                                        1
 +
rank_ligands
 +
You should be able to open the descriptor.output_scored.mol2 in Chimera using ViewDock.

Latest revision as of 10:09, 5 April 2021

Introduction

This tutorial is the second in a series of DOCK tutorials. For part I, please click here. De novo design, in practice, consists of two steps:

  • (1) fragment library generation and
  • (2) de novo construction.

DOCK directs ligand assembly in an iterative manner; structures are grown layer by layer as DOCK samples different fragments from the sidechain, linker, and scaffold libraries. In this tutorial, we will be performing two rounds of de novo design: once using a fragment library generated from the original ligand that was complexed with our receptor in the crystal structure, and once with a fragment library generated from many other druglike ligands.

Fragment Library Generation

Fragments are the basic unit of a molecule in DOCK_DN. In general, fragments will not contain any rotatable bonds, and are treated as rigid units. The general workflow for fragment library generation proceeds in the following manner:

  • Break the molecule(s) in the input file at each rotatable bond and insert dummy atoms at the point of cleavage.
  • Classify the resulting fragments as sidechains (which have one dummy atom), linkers (which have 2 dummy atoms), or scaffolds (which have three or more dummy atoms).

Software Requirements

In order to successfully follow this tutorial, please make sure to have the following programs installed:

We will be using a shell environment (either the built-in terminal for MacOS/Linux users or MobaXTerm for Windows users) to run several of the programs in this tutorial. As such, it may be useful to familiarize yourself with running basic UNIX commands and VIM.

In addition, this tutorial assumes you have access to a High Performance Computing cluster, i.e. Seawulf.

Directory Setup

Before we begin building our libraries, we should setup our directory structure: 

mkdir fraglib dn_focus dn_focus_rescore dn_generic dn_generic_rescore

Focused De Novo Design

Fragment Libraries

In the first part of the tutorial, we will be building a library of fragments out of our original ligand, the benzimidazol inhibitor. Move into the fraglib directory 

cd fragllib

Now create a new input file called fraglib.in. This file will be used for generating fragments. 

touch fraglib.in

Now interactively run the file in DOCK6: 

dock6 -i fraglib.in -o fraglib.out

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                                      12
internal_energy_cutoff                                       100.0
ligand_atom_file                                             1EFY_lig_with_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                                           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                                        fraglib.out
write_orientations                                           no
num_scored_conformers                                        1
rank_ligands                                                 no

The following files should have been generated: 

fraglib_linker.mol2, fraglib_rigid.mol2, fraglib_scaffold.mol2, fraglib_sidechain.mol2, 
fraglib_torenv.dat, fraglib.out_scored.mol2

Focused De Novo Growth

Next we will be performing the second step of the de novo process: growth. Move into the dn_focus directory. 

cd dn_focus

Create an input file for DOCK: 

touch focus.in

Run DOCK interactively: 

dock6 -i focus.in -o dn_focus.out
conformer_search_type                                        denovo
dn_fraglib_scaffold_file                                     ../fraglib/fraglib_scaffold.mol2
dn_fraglib_linker_file                                       ../fraglib/fraglib_linker.mol2
dn_fraglib_sidechain_file                                    ../fraglib/fraglib_sidechain.mol2
dn_user_specified_anchor                                     no
dn_use_torenv_table                                          yes
dn_torenv_table                                              ../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                                         550.0
dn_constraint_rot_bon                                        15
dn_constraint_formal_charge                                  2.0
dn_heur_unmatched_num                                        1
dn_heur_matched_rmsd                                         2.0
dn_unique_anchors                                            1
dn_max_grow_layers                                           9
dn_max_root_size                                             25
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                                        no
dn_output_prefix                                             dn_focus.out
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                                           ../fraglib/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                                       ../../../1EFY/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

Focused Denovo Rescore

Move into the dn_focus_rescore directory: 

cd dn_focus_rescore

Create the following input file: 

touch dn_rescore.in

Run the input file through DOCK interactively: 

dock6 -i dn_rescore.in

conformer_search_type                                        rigid
use_internal_energy                                          yes
internal_energy_rep_exp                                      12
internal_energy_cutoff                                       100.0
ligand_atom_file                                             ../dn_focus/dn_focus.out.denovo_build.mol2
limit_max_ligands                                            no
skip_molecule                                                no
read_mol_solvation                                           no
calculate_rmsd                                               no
use_database_filter                                          no
orient_ligand                                                no
bump_filter                                                  no
score_molecules                                              yes
contact_score_primary                                        no
contact_score_secondary                                      no
grid_score_primary                                           no
grid_score_secondary                                         no
multigrid_score_primary                                      no
multigrid_score_secondary                                    no
dock3.5_score_primary                                        no
dock3.5_score_secondary                                      no
continuous_score_primary                                     no
continuous_score_secondary                                   no
footprint_similarity_score_primary                           no
footprint_similarity_score_secondary                         no
pharmacophore_score_primary                                  no
pharmacophore_score_secondary                                no
descriptor_score_primary                                     yes
descriptor_score_secondary                                   no
descriptor_use_grid_score                                    no
descriptor_use_multigrid_score                               no
descriptor_use_continuous_score                              no
descriptor_use_footprint_similarity                          yes
descriptor_use_pharmacophore_score                           yes
descriptor_use_tanimoto                                      yes
descriptor_use_hungarian                                     yes
descriptor_use_volume_overlap                                yes
descriptor_fps_score_use_footprint_reference_mol2            yes
descriptor_fps_score_footprint_reference_mol2_filename       ../fraglib/1EFY.lig.min_scored.mol2
descriptor_fps_score_foot_compare_type                       Euclidean
descriptor_fps_score_normalize_foot                          no
descriptor_fps_score_foot_comp_all_residue                   yes
descriptor_fps_score_receptor_filename                       ../fraglib/1EFY_rec_dockprep.mol2
descriptor_fps_score_vdw_att_exp                             6
descriptor_fps_score_vdw_rep_exp                             12
descriptor_fps_score_vdw_rep_rad_scale                       1
descriptor_fps_score_use_distance_dependent_dielectric       yes
descriptor_fps_score_dielectric                              4.0
descriptor_fps_score_vdw_fp_scale                            1
descriptor_fps_score_es_fp_scale                             1
descriptor_fps_score_hb_fp_scale                             0
descriptor_fms_score_use_ref_mol2                            yes
descriptor_fms_score_ref_mol2_filename                       ../fraglib/1EFY.lig.min_scored.mol2
descriptor_fms_score_write_reference_pharmacophore_mol2      no
descriptor_fms_score_write_reference_pharmacophore_txt       no
descriptor_fms_score_write_candidate_pharmacophore           no
descriptor_fms_score_write_matched_pharmacophore             no
descriptor_fms_score_compare_type                            overlap
descriptor_fms_score_full_match                              yes
descriptor_fms_score_match_rate_weight                       5.0
descriptor_fms_score_match_dist_cutoff                       1.0
descriptor_fms_score_match_proj_cutoff                       0.7071
descriptor_fms_score_max_score                               20
descriptor_fingerprint_ref_filename                          ../fraglib/1EFY.lig.min_scored.mol2
descriptor_hms_score_ref_filename                            ../fraglib/1EFY.lig.min_scored.mol2
descriptor_hms_score_matching_coeff                          -5
descriptor_hms_score_rmsd_coeff                              1
descriptor_volume_score_reference_mol2_filename              ../fraglib/1EFY.lig.min_scored.mol2
descriptor_volume_score_overlap_compute_method               analytical
descriptor_weight_fps_score                                  1
descriptor_weight_pharmacophore_score                        1
descriptor_weight_fingerprint_tanimoto                       -1
descriptor_weight_hms_score                                  1
descriptor_weight_volume_overlap_score                       -1
gbsa_zou_score_secondary                                     no
gbsa_hawkins_score_secondary                                 no
SASA_score_secondary                                         no
amber_score_secondary                                        no
minimize_ligand                                              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
chem_defn_file                                               
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/chem.defn
pharmacophore_defn_file                                      
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/ph4.defn
ligand_outfile_prefix                                        descriptor.output
write_footprints                                             yes
write_hbonds                                                 yes
write_orientations                                           no
num_scored_conformers                                        1
rank_ligands                                                 no

The following files should have been generated: 

descriptor.output_footprint_scored.txt, descriptor.output_hbond_scored.txt, descriptor.output_scored.txt

Generic Denovo Growth

Generic Fragment Library

Move into the dn_generic_denovo directory: 

cd dn_generic_denovo

Create the following input file: 

touch gn_denovo.in

Run the input file interactively in DOCK: 

dock6 -i gn_denovo.in -o gn_denovo.out

conformer_search_type                                        denovo
dn_fraglib_scaffold_file                                     
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/fraglib_scaffold.mol2
dn_fraglib_linker_file                                       
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/fraglib_linker.mol2
dn_fraglib_sidechain_file                                    
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/fraglib_sidechain.mol2
dn_user_specified_anchor                                     no
dn_use_torenv_table                                          yes
dn_torenv_table                                              
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/fraglib_torenv.dat
dn_sampling_method                                           graph
dn_graph_max_picks                                           30
dn_graph_breadth                                             3
dn_graph_depth                                               2
dn_graph_temperature                                         100
dn_pruning_conformer_score_cutoff                            100
dn_pruning_conformer_score_scaling_factor                    1.0
dn_pruning_clustering_cutoff                                 100.0
dn_constraint_mol_wt                                         550.0
dn_constraint_rot_bon                                        15
dn_constraint_formal_charge                                  2.0
dn_heur_unmatched_num                                        1
dn_heur_matched_rmsd                                         2.0
dn_unique_anchors                                            1
dn_max_grow_layers                                           9
dn_max_root_size                                             25
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                                        no
dn_output_prefix                                             gn_denovo_output
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                                           ../fraglib/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                                           no
grid_score_secondary                                         no
multigrid_score_primary                                      no
multigrid_score_secondary                                    no
dock3.5_score_primary                                        no
dock3.5_score_secondary                                      no
continuous_score_primary                                     no
continuous_score_secondary                                   no
footprint_similarity_score_primary                           no
footprint_similarity_score_secondary                         no
pharmacophore_score_primary                                  no
pharmacophore_score_secondary                                no
descriptor_score_primary                                     yes
descriptor_score_secondary                                   no
descriptor_use_grid_score                                    yes
descriptor_use_pharmacophore_score                           no
descriptor_use_tanimoto                                      no
descriptor_use_hungarian                                     no
descriptor_use_volume_overlap                                no
descriptor_grid_score_rep_rad_scale                          1
descriptor_grid_score_vdw_scale                              1
descriptor_grid_score_es_scale                               1
descriptor_grid_score_grid_prefix                            ../../../1EFY/003.gridbox/grid
descriptor_weight_grid_score                                 1
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

Generic Denovo Rescore

Move into the dn_generic_rescore directory 

cd dn_generic_rescore

Create the following input file: 

touch gn_rescore.in

Run the input file interactively in DOCK: 

dock6 -i gn_rescore.in -o gn_resocre.out

conformer_search_type                                        rigid
use_internal_energy                                          yes
internal_energy_rep_exp                                      12
internal_energy_cutoff                                       100.0
ligand_atom_file                                             ../11_dn_focus/dn_generic.out.denovo_build.mol2
limit_max_ligands                                            no
skip_molecule                                                no
read_mol_solvation                                           no
calculate_rmsd                                               no
use_database_filter                                          no
orient_ligand                                                no
bump_filter                                                  no
score_molecules                                              yes
contact_score_primary                                        no
contact_score_secondary                                      no
grid_score_primary                                           no
grid_score_secondary                                         no
multigrid_score_primary                                      no
multigrid_score_secondary                                    no
dock3.5_score_primary                                        no
dock3.5_score_secondary                                      no
continuous_score_primary                                     no
continuous_score_secondary                                   no
footprint_similarity_score_primary                           no
footprint_similarity_score_secondary                         no
pharmacophore_score_primary                                  no
pharmacophore_score_secondary                                no
descriptor_score_primary                                     yes
descriptor_score_secondary                                   no
descriptor_use_grid_score                                    no
descriptor_use_multigrid_score                               no
descriptor_use_continuous_score                              no
descriptor_use_footprint_similarity                          yes
descriptor_use_pharmacophore_score                           yes
descriptor_use_tanimoto                                      yes
descriptor_use_hungarian                                     yes
descriptor_use_volume_overlap                                yes
descriptor_fps_score_use_footprint_reference_mol2            yes
descriptor_fps_score_footprint_reference_mol2_filename       ../fraglib/1EFY.lig.min_scored.mol2
descriptor_fps_score_foot_compare_type                       Euclidean
descriptor_fps_score_normalize_foot                          no
descriptor_fps_score_foot_comp_all_residue                   yes
descriptor_fps_score_receptor_filename                       ../fraglib/1EFY_rec_dockprep.mol2
descriptor_fps_score_vdw_att_exp                             6
descriptor_fps_score_vdw_rep_exp                             12
descriptor_fps_score_vdw_rep_rad_scale                       1
descriptor_fps_score_use_distance_dependent_dielectric       yes
descriptor_fps_score_dielectric                              4.0
descriptor_fps_score_vdw_fp_scale                            1
descriptor_fps_score_es_fp_scale                             1
descriptor_fps_score_hb_fp_scale                             0
descriptor_fms_score_use_ref_mol2                            yes
descriptor_fms_score_ref_mol2_filename                       ../fraglib/1EFY.lig.min_scored.mol2
descriptor_fms_score_write_reference_pharmacophore_mol2      no
descriptor_fms_score_write_reference_pharmacophore_txt       no
descriptor_fms_score_write_candidate_pharmacophore           no
descriptor_fms_score_write_matched_pharmacophore             no
descriptor_fms_score_compare_type                            overlap
descriptor_fms_score_full_match                              yes
descriptor_fms_score_match_rate_weight                       5.0
descriptor_fms_score_match_dist_cutoff                       1.0
descriptor_fms_score_match_proj_cutoff                       0.7071
descriptor_fms_score_max_score                               20
descriptor_fingerprint_ref_filename                          ../fraglib/1EFY.lig.min_scored.mol2
descriptor_hms_score_ref_filename                            ../fraglib/1EFY.lig.min_scored.mol2
descriptor_hms_score_matching_coeff                          -5
descriptor_hms_score_rmsd_coeff                              1
descriptor_volume_score_reference_mol2_filename              ../fraglib/1EFY.lig.min_scored.mol2
descriptor_volume_score_overlap_compute_method               analytical
descriptor_weight_fps_score                                  1
descriptor_weight_pharmacophore_score                        1
descriptor_weight_fingerprint_tanimoto                       -1
descriptor_weight_hms_score                                  1
descriptor_weight_volume_overlap_score                       -1
gbsa_zou_score_secondary                                     no
gbsa_hawkins_score_secondary                                 no
SASA_score_secondary                                         no
amber_score_secondary                                        no
minimize_ligand                                              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
chem_defn_file                                               /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/chem.defn
pharmacophore_defn_file                                      /gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/ph4.defn
ligand_outfile_prefix                                        descriptor.output
write_footprints                                             yes
write_hbonds                                                 yes
write_orientations                                           no
num_scored_conformers                                        1
rank_ligands

You should be able to open the descriptor.output_scored.mol2 in Chimera using ViewDock.

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