Subject: Re: CCL:Binding energy

From: Szilveszter JUHOS <szilveszter.juhos*at*chemaxon.hu>
Date: Sat, 7 Aug 2004 10:06:30 +0200 (CEST)

On Fri, 6 Aug 2004, Pandey, Jaya wrote:
> I screened about 1900 small ligands using AutoDock and the lowest energy of
> binding I could get was -10.00. Is it worth trying this ligand in the lab?

Dear Jaya,

Welcome to the docking club! ;) As you are writing -10, it does not mean
too much (like I am saying that is is 22 C outside, but is it cold or
warm?  Depends... ) . My (personal) view would be that

i) 1900 candidates are rather few if you are not working with a ligand set
that is focussed on your particular target. For example if it a carefully
selected kinase library and you are targeting a kinase, probably this
amount is a minimum to start docking with. I would consider 100K filtered
ligand at least or more.

ii) lowest energy does not necessarily mean it is the best binding ligand:
the relationship between the calculated and real dG is not always linear
and there is a quite a lot error both in measuring and calculating dG

iii) the ligand can be too "sticky": full of H-bond donors/acceptors and
happy to bind anywhere to polar surface with high affinity (pre-filtering
comes here)

iv) check carefully wether are there "bad contats" not penalised by the
scoring function. Typical things are lone pairs facing to each
other, voids between the ligand and the target

v) the ligand can face its apolar part towards the solvent

vi) if there is a chance do not try only the best scoring one but a
diverse subset of the good scoring ones.

and it goes on like this. Sometimes it is worth to have a look to known
complexes (like the GOLD/Astex and the Glide set), check the polarity of
the cavity, position of aromatic rings/stacks etc. just to train you eyes.

> Another query is that how to improve the binding energy.

What about having few candidates, creating a diverse set based
on these molecules and re-docking them?

> Please advice and help, what kind of energy one should look for to get a
> lead?

This a multi-million dollar question :) .. I wish I knew the answer! I
would say (again: personel view) docking is not the best for lead
development but god for hit-identification. Once you have a dozen or two
diverse hits you can play a lot with other tools/experiments to get
two-three leads.

Szilva