De novo Developer Progress

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This is the Rizzo lab wiki page for coordinating bugs and progress on the de novo project.

Version of the code on cluster that we should be using:


This version includes the orienting fragments fix, and rotatable bond fix.

DOCK6.8 merge: de novo and dock6.8 were merged (/gpfs/home/leprentis/dock6.8_merge_06.14.2017)

Path to Generic Fragment Library:


Path to Frequency Anchors:


Current Coding Issues:

Working on these currently:

  1. Lauren: Check 663 (5through15_ch2) systems with merged dock6.8 and check analysis against de novo paper analysis.
  2. Lauren: Fix Frag_String output into chimera for refinement situations
  3. Lauren: Implement Roulette fragment picking into graph and random as an option
  4. Lauren: Change scaling factor to a function of decay (currently a straight line to lowest score cutoff)
  5. Lauren: Test simple build function with merged de novo
  6. Lauren: Testing with sb2012 default values for molecules passed on to the next layer and root (looking for timing and efficiency).
  7. Steven: editting script to calculate SMILE string of de novo molecules in OpenBable

Not working on these right now:

  1. Lauren: Adjacency matrix vs tors env
  2. Lauren: Addition of "3mer" combination fragment check (post tors check)
  3. Lauren: Min and Max for charge to replace absolute value of charge.(Dwight suggestion)
  4. Lauren: Capping groups for post growth process (halogens and methyls)


  1. Lauren: Implement csingleton fix for orienting fragments with less than 3 heavy atoms
  2. Lauren: Test bfochtman fix for rotatable bonds within an user defined anchor

List of features that we definitely want for the 6.8 release:

Task Owner Complete?
Smooth pruning scaling function LEP
Roulette function to Random and Graph as an option LEP
Overhaul the simple build function LEP
When minimizing with descriptor score, make sure fingerprint is turned off xxx
Speed up fingerprint calculations by saving reference ligand as a permanent object WJA yep
Add pre-min conformations to growth trees WJA yep
Add verbose flag options WJA yep
Put molecular properties (RB, MW, etc) in mol2 header WJA yep
Put ensemble properties (RB, MW, etc) output stream at the end of each layer WJA yep
Check formal charge prune BCF yep
Combination of horizontal pruning metrics (let's consider dropping tanimoto prune and just using hungarian prune) WJA yep
Finish implementing growth trees WJA yep
Revisit orienting to make sure it is working as intended WJA yep
Fixed a bug where we were marking scaffold_this_layer as true for any fragment WJA yep
Update random sampling function to use last layer changes in graph function WJA yep
Do that same thing for the exhaustive function WJA yep
I don't think we ever clear the scaf_link_sid vector, we definitely should do that somewhere WJA yep
Update exhaustive to combine all frags into one library, just like graph / random. WJA yep

List of features/ideas for future releases:

  • Stereo centers / volume overlap pruning
  • Capping group functions (H, CH3, Halogen)
  • Incorporate GA at the end of each layer
  • Overhaul the simple-build function
  • Monte carlo algorithm that checks bond frequency
  • Scaling max root / layer size with layer
  • Select torenv before selecting fragment. Will need to overhaul fraggraph, will keep us from needing to assemble mols that will not pass torenv.
  • Add fragname string to restart and dump files, already done for final and fraglib files.
  • Add ZINC name to torenv table
  • Unusual behavior during library generation when frequency cutoff == 0
  • Print out how many molecules cannot be capped. (Difference between ensemble size and dump.)
  • building from anchor 0 -> building from scf.98
  • Possible torenv check for dump molecules after capping before printing.

List of SB2012 systems that we will use for tests:

For now, let's use 5-15 rotatable bonds inclusive; total = 709 systems ("drug-like" size molecules). De novo paper only used 663 systems that removed 46 systems where the cognate ligand did not fall with a +/-2 formal charge. (5through15 = 709, 5through15_ch2 = 663)

{5RB = 107; 6RB = 96; 7RB = 103; 8RB = 75; 9RB = 66; 10RB = 75; 11RB = 57; 12RB = 41; 13RB = 38; 14RB = 26; 15RB = 25}

The input file we should be using:

Note: these are currently all the defaults (except for scoring function). Once we figure out the best set of parameters for both (1) focused and (2) generic libraries, then we need to update the defaults accordingly.

conformer_search_type                                        denovo
dn_fraglib_scaffold_file                                     fraglib_scaffold.mol2
dn_fraglib_linker_file                                       fraglib_linker.mol2
dn_fraglib_sidechain_file                                    fraglib_sidechain.mol2
dn_user_specified_anchor                                     yes
dn_fraglib_anchor_file                                       fraglib_anchor.mol2
dn_use_torenv_table                                          yes
dn_torenv_table                                              torenv_table.dat
dn_sampling_method                                           graph
dn_graph_starting_points                                     10
dn_graph_breadth                                             5
dn_graph_depth                                               2
dn_graph_temperature                                         100.0
dn_pruning_conformer_score_cutoff                            100.0
dn_pruning_conformer_score_scaling_factor                    1
dn_pruning_clustering_cutoff                                 100.0
dn_constraint_mol_wt                                         1000.0
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                                            3
dn_max_grow_layers                                           9
dn_max_root_size                                             100
dn_max_layer_size                                            100
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                                             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                                           receptor.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
ph4_score_primary                                            no
ph4_score_secondary                                          no
descriptor_score_primary                                     yes
descriptor_score_secondary                                   no
descriptor_use_grid_score                                    no
descriptor_use_multigrid_score                               yes
descriptor_use_pharmacophore_score                           no
descriptor_use_tanimoto                                      yes
descriptor_use_hungarian                                     yes
descriptor_multigrid_score_rep_rad_scale                     1
descriptor_multigrid_score_vdw_scale                         1
descriptor_multigrid_score_es_scale                          1
descriptor_multigrid_score_number_of_grids                   N
descriptor_multigrid_score_grid_prefix0                      grid0
descriptor_multigrid_score_grid_prefixN-2                    gridN
descriptor_multigrid_score_grid_prefixN-1                    grid_remaining
descriptor_multigrid_score_fp_ref_mol                        yes
descriptor_multigrid_score_footprint_ref                     ../001.files/8ABP.lig.multigridmin.mol2
descriptor_multigrid_score_use_euc                           yes
descriptor_multigrid_score_use_norm_euc                      no
descriptor_multigrid_score_use_cor                           no
descriptor_multigrid_vdw_euc_scale                           1
descriptor_multigrid_es_euc_scale                            1
descriptor_fingerprint_ref_filename                          ../001.files/8ABP.lig.multigridmin.mol2
descriptor_hungarian_ref_filename                            ../001.files/8ABP.lig.am1bcc.mol2
descriptor_hungarian_matching_coeff                          -5
descriptor_hungarian_rmsd_coeff                              1
descriptor_weight_multigrid_score                            1
descriptor_weight_fingerprint_tanimoto                       0
descriptor_weight_hungarian                                  0
gbsa_zou_score_secondary                                     no
gbsa_hawkins_score_secondary                                 no
SASA_descriptor_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                                                vdw.defn
flex_defn_file                                               flex.defn
flex_drive_file                                              flex_drive.tbl