[Dock-fans] Fixing protonation state

John J. Irwin jji at cgl.ucsf.edu
Thu Nov 1 14:35:37 PDT 2007

Hi Francesco

Here are three arguments to try to convince you that big floppy
molecules make poor candidates for docking.

[I was unaware of the target of that compound, and based my comments
about the unsuitability for docking purely upon the molecule itself. ]

1. The number of conformations to be sampled goes up exponentially as a
function of the number of rotatable bonds. Let's assume three
conformations around each bond for the sake of simplicity. Thus 3^7 =
2187 , 3^10 = 59,049 and  3^17 = 129,140,163. These are the number of
conformations to be sampled, even by very coarse sampling, for molecules
with 7, 10 and 17 rotatable bonds, respectively. That's very coarse,
fix-interval sampling. At 1 second per conformation (and that's
considered fast by the standards of the field) that makes 4.1 years for
17 rotatable bonds. for one *%^* molecule.

2. If you have a molecule like the one suggested by Asdrubal, a
"dumbell" with 19 bonds between the aromatics at the end, then a
movement of just a degree or two around the central bond can result in a
relative shift of the extremities (and thus the overall shape of the
molecule) by 5A or more. This hypersensitivity of shape to central bonds
means that you cannot hope to sample all the "right" conformation given
fixed increment angle sampling, which is all you can afford to do. If
you try to sample more finely, say 10 angles around a bond instead of 3,
then you're stuck with 10^17 conformations. Even being clever and doing
10 points around central bonds decreasing to 3 points at the extremities
would necessitate sampling an implausibly large number of conformations.

3. This molecule has terrible entropy problems. It is common practice to
remove molecules from virtual screening libraries with more than 6
methylene's in a row, for this reason. Large numbers of rotatable bonds
tend to have bioavailability problems too (Veber, J Med Chem, 2002), in
case you are still unconvinced.

By the way, there are many drugs that break the rules I just laid
outlined. I am not saying these molecules cannot be drugs. I am saying
they are problematic candidates for molecular docking, and very likely,
as *starting points* for ligand discovery.

I hope this is clear and helpful.


Francesco Pietra wrote:
> Is your skepticism only about the precision of docking (with large, flexible
> molecules) or is any evidence that also the region of receptor where docking is
> found may be false? E.g. helix S5 instead of S6 in a pore?
> Thanks
> francesco pietra
> --- "John J. Irwin" <jji at cgl.ucsf.edu> wrote:
>> Hi Asdrubal
>> That molecule has more rotatable bonds (13 in a row, 17 total, + limited
>> sampling on the 2 amides) than I feel comfortable with. It also has
>> molecular weight > 600. These are two reason why the ZINC upload server
>> just won't take it. I have to draw the line somewhere, and I regret to
>> say you have hit it.
>> I would be skeptical of anyone who docks a molecule having 17 (or even
>> 13) rotatable bonds and gets the crystallographic pose within 2A rmsd.
>> Actually, my skepticism starts at around 8 rotatable bonds, but I keep
>> it mostly to myself till we get past 12. ;-)
>> Almost for sure, you are trying to dock into two distinct pockets, and
>> the long aliphatic chain is a linker between them. My suggestion is
>> therefore to dock each end separately. Shoot for something with 7
>> rotatable bonds, even a bit less if you can. Then you can model in the
>> rest of the linker between them.
>> Good luck, and sorry to disappoint.
>> John
>> burgosgu at ualberta.ca wrote:
>>> Hi everybody,
>>> I need to have a compound correctly protonated to dock it. I tried to  
>>> use the resource of
>>> "upload sets" of ZINC, but it seems that it does not have the required  
>>> charactersitics of
>>> bioavailability and non-toxicity, because it gives me no output as it  
>>> did with other
>>> compounds.
>>> The smile for this compound is:
>>> Any suggestions??
>>> Asdrubal
>>> _______________________________________________
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>>> Dock-fans at docking.org
>>> http://blur.compbio.ucsf.edu/mailman/listinfo/dock-fans
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