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

These fragments can also be visualized in Chimera. The results are shown below.

2p16 fragments. The left image is the side chain fragments. The center are the scaffold fragments and the left is the linker.

Focused Denovo Growth

Focused Denovo Rescore

Generic Denovo Design with PDB 1S19