2022 Denovo tutorial 2 with PDBID 4ZUD

From Rizzo_Lab
Revision as of 12:48, 28 February 2022 by Stonybrook (talk | contribs)
Jump to: navigation, search

De Novo Design

De novo design refers to the process of generating novel ligands in an effort to identify molecules of physiological significance that can be further optimized to become approved drug molecules. The synthesis of thousands of potential drug molecules are done experimentally daily, but with computers, millions of molecules can be computationally modelled and pre-selected for possible synthesis in a fraction of the time it would take to test all possible molecules solely experimentally. With this, scientists are able to direct their attention towards molecules that have the highest probability of imparting a therapeutic effect upon binding to a respective receptor.

This tutorial is the second part of the 2022 DOCK tutorial 2 with PDBID 4ZUD tutorial. You will need the files created in that tutorial to continue with this one!

Make a new directory to organize the files generated in this tutorial:

mkdir 005.denovo

Fragment Library Generation

To create new molecules, we need to begin with the building blocks. For the purposes of speed, we most often use pre-defined molecular fragments that can be arranged/attached in a variety of orientations to create unique structures. Since we have the structure of a ligand that is known to bind the 4ZUD protein, we can generate fragments from that molecule to increase the probability of creating molecules with similar properties to the known ligand.

In an input file:

vim fragment.in

Insert 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                                no
use_internal_energy                                          yes
internal_energy_rep_exp                                      12
internal_energy_cutoff                                       100.0
ligand_atom_file                                             ../001.structure/4ZUD_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                                        fragment.out
write_orientations                                           no
num_scored_conformers                                        1
rank_ligands                                                 no

Run the fragment generation with the following command:

dock6 -i fragment.in -o fragment.out

DOCK should generate six files; three of those files should be mol2's of linker, scaffold, and side chain fragments. You can extract the number of fragments present in each file by running:

grep -wc MOLECULE *.mol2

Focused De Novo Growth

Focused De Novo Rescored