2021 Denovo tutorial 3 with PDBID 1S19

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This tutorial continues where we left off from the virtual screening of 1S19, a structure of the vitamin D nuclear receptor bound to the side chain analogue calcipotriol.

Focused Denovo Design with PDB 1S19

In this section, we will generate new ligand structures using a fragment library. It will require the use of some of the output files from the Virtual Screen tutorial (found here).

Fragment Libraries

We will use a focused fragment library file based on the original ligand. To begin, we will create a new directory for this.

mkdir fraglib

Create a new file called fragment.in with the following inputs.

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                                             ../001_structure/1s19_ligand_dockprep.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
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                                        fragment.out
write_orientations                                           no
num_scored_conformers                                        1
rank_ligands                                                 no

To run this, type:

dock6 -i fragment.in -o fragment.out

Once this has ran, the following files should have been generated: fraglib_linker.mol2, fraglib_rigid.mol2, fraglib_scaffold.mol2, fraglib_sidechain.mol2, fraglib_torenv.dat. To check the number of fragments in each file, you can type:

grep -wc MOLECULE *.mol2

Focused Denovo Growth

Focused Denovo Rescore

Generic Denovo Design with PDB 1S19