2020 Denovo tutorial 1 with PDBID 3VJK

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.