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.
Next, we will make an input file for dock
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.
We will be now conducting focus denovo.
mkdir 017.focused_denovo/ cd 017.focused_denovo/