[Dock-fans] use_clash_overlap and use_internal_energy

[Jerry Parks]

John

All the results I mentioned in my previous email were obtained with DOCK
v6.2.

You have a good point about just buying the compounds, but apparently our
experimental collaborators want to make at least some of them on their
own. I guess it's good synthesis practice for the grad students.

So, do you see any obvious input file errors that could be fixed so that
we get more realistic geometries? Would we need to use AMBER Score to
prevent the intramolecular ligand clashes?

Thanks,
Jerry

On Wed, 11 Jun 2008, John J. Irwin wrote:

> Hi Jerry
>
> Are you using the latest version, DOCK 6.2 ?
>
> I hope you will not have to synthesize compounds, but just buy them.
> That is the whole point of ZINC - to shorten the hypothesis-test cycle.
>
> Good luck.
>
> John
>
>
> Jerry Parks wrote:
> > Hello
> >
> > We have been using anchor-and-grow to perform flexible docking and
> > minimization on a large number of compounds from the zinc7 database. Many
> > of the highest scoring compounds suffer from geometries with unreasonable,
> > overlapping functional groups and rings. I really don't think we can trust
> > the results we've obtained thus far.
> >
> > Our goal is to generate leads via docking, then synthesize approximately
> > 20-50 molecules and assay them to determine if they are in fact
> > inhibitors.
> >
> > I have seen previous posts regarding "interpenetrated" structures, etc.,
> > but I'm still not sure how to circumvent this problem. It seems to me that
> > use_internal_energy should prevent these types of overlaps if the
> > repulsive vdw exponent is in effect. Any help/advice would be appreciated.
> >
> > I have attached a representative input file below.
> >
> > Thanks,
> > Jerry
> >
> > --------------------
> >
> > ligand_atom_file                     test-8.mol2
> > limit_max_ligands                    no
> > skip_molecule                        no
> > read_mol_solvation                   no
> > calculate_rmsd                       no
> > orient_ligand                        yes
> > automated_matching                   yes
> > receptor_site_file                   ../selected_spheres.sph
> > max_orientations                     500
> > critical_points                      no
> > chemical_matching                    no
> > use_ligand_spheres                   no
> > flexible_ligand                      yes
> > min_anchor_size                      40
> > pruning_use_clustering               yes
> > pruning_max_orients                  100
> > pruning_clustering_cutoff            100
> > use_internal_energy                  yes
> > internal_energy_att_exp              6
> > internal_energy_rep_exp              12
> > internal_energy_dielectric           4.0
> > use_clash_overlap                    yes
> > clash_overlap                        0.50
> > bump_filter                          no
> > score_molecules                      yes
> > contact_score_primary                no
> > contact_score_secondary              no
> > grid_score_primary                   yes
> > grid_score_secondary                 no
> > grid_score_rep_rad_scale             1
> > grid_score_vdw_scale                 1
> > grid_score_es_scale                  1
> > grid_score_grid_prefix               ../grid_999_10
> > dock3.5_score_secondary              no
> > continuous_score_secondary           no
> > gbsa_zou_score_secondary             no
> > gbsa_hawkins_score_secondary         no
> > amber_score_secondary                no
> > minimize_ligand                      yes
> > minimize_anchor                      yes
> > minimize_flexible_growth             yes
> > use_advanced_simplex_parameters      no
> > simplex_max_cycles                   1
> > simplex_score_converge               0.1
> > simplex_cycle_converge               1.0
> > simplex_trans_step                   1.0
> > simplex_rot_step                     0.1
> > simplex_tors_step                    10.0
> > simplex_anchor_max_iterations        500
> > simplex_grow_max_iterations          500
> > simplex_final_min                    no
> > simplex_random_seed                  0
> > atom_model                           all
> > vdw_defn_file                        ../vdw_AMBER_parm99.defn
> > flex_defn_file                       ../flex.defn
> > flex_drive_file                      ../flex_drive.tbl
> > ligand_outfile_prefix                test-8
> > write_orientations                   no
> > num_scored_conformers_written        1
> > rank_ligands                         yes
> > max_ranked_ligands                   500
> >
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> > Dock-fans at docking.org
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> >
>