ADL: question about Vina flexible residues and pockets

Dennis N Bromley dbromley at uw.edu
Wed Jan 22 13:39:34 PST 2014


ok, thank you Oleg, I really appreciate it.
-denny-





On Wed, Jan 22, 2014 at 1:18 PM, Oleg Trott <trott at scripps.edu> wrote:

> Hi
>
> If you have known binders for your pocket, as I thought you did, a
> retrospective VS is what one would do to evaluate a VS protocol.
>
> If you don't, perhaps you can extrapolate the results from homologous
> proteins with known binders (but I guess it comes down to user's
> intuition and experience, as I don't know of any quantitative models
> for this)
>
> If, in the worst case, you have no known binders for your pocket, and
> no relevant information from homologous proteins, I don't think there
> is much you can do to predict if a VS will turn out to be useful for
> your system: perhaps it will work brilliantly, or perhaps it will have
> < 1 enrichment (worse than random guessing).
>
> The conventional wisdom is that the "baseline" for good binders would
> vary depending on the pocket.
>
> HTH
>
>
> On Wed, Jan 22, 2014 at 10:39 AM, Dennis N Bromley <dbromley at uw.edu>
> wrote:
> > Thank you, Oleg, this is useful. I appreciate your time.
> >
> > So far as I know, there is only one known binder for my system and that
> is
> > in a completely different pocket, so I don't really have a set of
> > comparables for this protein. (That known binder docks at -6.5 kcal/mol,
> so
> > I was interpreting that as a baseline.)  I was basically planning to use
> > Vina as a high-throughput pipeline to test lots of different ZINC ligands
> > and see if I could zero in on good ones.  My problem is that every
> ligand I
> > pick seems 'good', at least by the baselines that I have found.
> >
> > So, I apologize if I am not understanding you.  Do you see a problem in
> my
> > previous approach or assumptions?  Or are you saying that before I can
> > begin my previous approach I need to do some preliminary work that I
> > haven't mentioned?
> >
> > thanks!
> > -denny-
> >
> >
> >
> >
> >
> > On Wed, Jan 22, 2014 at 10:21 AM, Oleg Trott <trott at scripps.edu> wrote:
> >
> >> ... Incidentally, Vina does really well on the COX-2 target in the
> >> Directory of Useful Decoys:
> >>
> >> http://docking.utmb.edu/dudresults/overlaid/CycloOxygenase2.png
> >>
> >> Only GLIDE HTVS does somewhat better.
> >>
> >> On Wed, Jan 22, 2014 at 10:10 AM, Oleg Trott <trott at scripps.edu> wrote:
> >> > Hi
> >> >
> >> > I'm assuming that you want to evaluate the suitability of Vina as a
> >> > virtual screening method for your system.
> >> >
> >> > To do that, you could do a retrospective VS on known binders and
> >> > either known non-binders or random decoys, kind of like what the
> >> > Directory of Useful Decoys offers (Vina results linked from the Vina
> >> > web site and manual). If it sounds too tedious to do by hand, I think
> >> > PyRX can automate it, and make ROC plots for you.
> >> >
> >> > The ease of fishing for a few predicted bad binders seems difficult to
> >> > interpret.
> >> >
> >> > "Score_only" of X-ray structures probably shouldn't be used to
> >> > estimate the binding affinity: for all we know, there is a 10kcal/mol
> >> > better energy 0.1A RMSD next to it. (Also, it's believed that about
> >> > 1/3 of all bound ligand X-ray structures are completely wrong)
> >> >
> >> > On Wed, Jan 22, 2014 at 9:24 AM, Dennis N Bromley <dbromley at uw.edu>
> >> wrote:
> >> >> Hi everyone,
> >> >>
> >> >> I am having a problem because practically any ligand that I throw at
> my
> >> >> pocket seems to dock with reasonable energy and it seems that that
> >> should
> >> >> not be the case.  Here is what I am doing:
> >> >>
> >> >> I used a pocket-finding algorithm (epos ball-pass) to find a pocket
> in
> >> my
> >> >> protein and now I want to use Vina to find a ligand that will bind
> >> tightly
> >> >> to it.  I set my search box to be centered around the pocket plus an
> >> extra
> >> >> 5 angstroms in each direction for padding.  I then set all of the
> >> >> pocket-lining residues to be flexible, convert a huge stack of ZINC
> >> ligands
> >> >> to pdbqt using OpenBabel, and dock them in.  My pocket is ~430 cubic
> >> >> angstroms.
> >> >>
> >> >> To date, the worst energy I have gotten is -5.9 kcal/mol.  The best I
> >> have
> >> >> gotten is -12.1 kcal/mol.  For reference, the drug celebrex in xtal
> holo
> >> >> position docks into COX-2 (PDB:3LN1) with -10.6 kcal/mol (using
> >> >> --score-only) and various bits of literature show Vina energies of
> >> vitamins
> >> >> and such around -9.  So, these values seem like they might actually
> >> >> potentially bind.
> >> >>
> >> >> The problem is that I can't find a bad docker for the life of me,
> which
> >> >> makes me question my good dockers.  My pocket is an internal pocket
> in
> >> the
> >> >> hydrophobic core of the protein (as is my comparable, Celebrex) so I
> >> >> searched ZINC for the most awkward polar molecule I could find and it
> >> still
> >> >> came in at -9 kcal/mol.  I can't even match my -5.9 molecule;
> literally
> >> >> random picks still score in the -7 to -8 range.
> >> >>
> >> >> Any ideas what I am doing wrong?  Am I misinterpreting "good energy"?
> >> >>  Should I not be using flexible residues?  There are about twenty
> >> residues
> >> >> in the pocket - does that provide so much freedom that it will adjust
> >> for
> >> >> just about any ligand?
> >> >>
> >> >>
> >> >> Thank you!  I appreciate any insights - something is amiss here that
> I
> >> am
> >> >> not seeing.
> >> >> Denny
> >> >> ________________________________________________
> >> >> --- ADL: AutoDock List  ---
> http://autodock.scripps.edu/mailing_list---
> >> >
> >> >
> >> >
> >> > --
> >> > Oleg Trott, Ph.D. (Columbia University)
> >> >
> >> > Staff Scientist in the Olson Lab
> >> > The Scripps Research Institute
> >> >
> >> > http://olegtrott.com
> >>
> >>
> >>
> >> --
> >> Oleg Trott, Ph.D. (Columbia University)
> >>
> >> Staff Scientist in the Olson Lab
> >> The Scripps Research Institute
> >>
> >> http://olegtrott.com
> >> ________________________________________________
> >> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list---
> >>
> > ________________________________________________
> > --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
>
>
>
> --
> Oleg Trott, Ph.D. (Columbia University)
>
> Staff Scientist in the Olson Lab
> The Scripps Research Institute
>
> http://olegtrott.com
> ________________________________________________
> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
>


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