From owner-chemistry@ccl.net Thu Jun 17 03:17:00 2010
From: "Kalju Kahn kalju.:.chem.ucsb.edu" <owner-chemistry . server.ccl.net>
To: CCL
Subject: CCL: Docking Software for Macrocycles
Message-Id: <-42128-100617031548-899-RfXnB0r2drVyhZfpbeaQWA . server.ccl.net>
X-Original-From: "Kalju Kahn" <kalju.:.chem.ucsb.edu>
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Date: Thu, 17 Jun 2010 00:14:49 -0700
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Sent to CCL by: "Kalju Kahn" [kalju!=!chem.ucsb.edu]
John,
Could you turn the order around: do a conformational analysis of the
scaffold (with possible restraints dictated by the shape of the binding
pocket), then create a virtual library of compounds by substituting into
the macrocycle using a set of low-energy conformers. I think Helgi
Adalsteinsson (Bioorganic & Medicinal Chemistry 8 (2000) 625-635) tried
something like this. He also wrote some scripts to automate this process.
Hope this helps,
Kalju
>
> Sent to CCL by: "John Furr" [john.furr|gmail.com]
> Hey gang,
>
> I'm looking for advise/tips about docking software that will work well
> with large macrocycles...19+ ring atoms. Software can be commercial or
> not.
>
> Currently we are using the Schrodinger suite of tools with moderate
> success. However our biggest limitation is that glide does not sample
> large ring conformations. This means that for every compounds we want to
> dock we have to first do an upfront conformational analysis and this takes
> several hours to do in a complete manner.
>
> To put it in units of time. It takes me about 4 hours per compound to get
> a docked pose for a single CPU. There are literally times that the
> chemistry team is faster than me!
>
> Obviously we are very interested in exploring other options that would
> allow us to improve our throughput without compromising robustness.
>
> So gang any advise and or tips?
>
> Cheers
> John Furr>
>
>
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Dr. Kalju Kahn
Department of Chemistry and Biochemistry
UC Santa Barbara, CA 93106
From owner-chemistry@ccl.net Thu Jun 17 08:30:00 2010
From: "Vincent Leroux vincent.leroux:loria.fr" <owner-chemistry===server.ccl.net>
To: CCL
Subject: CCL: Entropy in docking
Message-Id: <-42129-100616214953-2010-giQin7GEz65XNRzxVM89Pg===server.ccl.net>
X-Original-From: Vincent Leroux <vincent.leroux ~ loria.fr>
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Date: Thu, 17 Jun 2010 02:52:48 +0200
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Sent to CCL by: Vincent Leroux [vincent.leroux]~[loria.fr]
Hi Nikolay,
Most docking programs scoring functions so simplistic that they are not
on the same level of theory as anything dealing with entropy... So
during the docking process, entropy is not explicitly taken into account.
A typical scoring function will have at least three terms:
- one accounting for the "direct" protein-ligand interactions
(electrostatics, hydrogen bonds...)
- an internal ligand penalty for avoiding unrealistic conformations
- the 3rd term, even more empirically parameterized than the two others,
is related to the "desolvation effect".
If docking scoring functions could be considered as rigorous measures of
the free energy of binding, the entropy would be located in the latter.
With such simple scoring functions, it is being assumed that a ligand
"filling space" on a protein receptor "liberates" the waters that were
there* from an entropically-restricted* state, releasing them into a
more favorable* "bulk solvent" state, the most "hydrophobic" the active
site surface and the ligand shape fitting it the better* the energetic
gain, and that this dominates* the entropic contribution in the whole
ligand binding process (* indicating assumptions that can be heavily
challenged).
You might use docking to get a set (1-10, not hundreds) of acceptable
starting conformations before more complex simulations that will
possibly account for entropy. Some of such post-docking optimizations
might be included and automated in the docking program itself (Glide
being the most well-known example here). In any case, the docking
scoring function is dumped, usually for a forcefield-based potential.
For estimating entropy rigorously extensive sampling is required,
preferably with the protein-ligand system modeled in explicit water.
Regards
VL
Le 16/06/10 19:11, Nikolay Novikov nikolay_novikov%%yahoo.com a �crit :
> Sent to CCL by: "Nikolay Novikov" [nikolay_novikov : yahoo.com]
> Dear CCL members,
>
> Would you advice me on how to account for entropy in protein-ligand docking? What software is used to account for entropy when docking yields several hundreds of docked positions?
> Thank you all!
>
> Sincerely,
> Nikolay Novikov
> Ph.D. student,Lviv University,
> Ukraine>
>
>
From owner-chemistry@ccl.net Thu Jun 17 13:14:00 2010
From: "John john{:}ccdc.cam.ac.uk" <owner-chemistry[-]server.ccl.net>
To: CCL
Subject: CCL: Docking Software for Macrocycles
Message-Id: <-42130-100617081934-2117-IY0NyV7+o80CQH+/S8gyow[-]server.ccl.net>
X-Original-From: "John" <john*|*ccdc.cam.ac.uk>
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Date: Thu, 17 Jun 2010 09:58:23 +0100
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Sent to CCL by: "John" [john{:}ccdc.cam.ac.uk]
Dear John,
GOLD can handle macrocycle docking but you will need to
calculate a ring template library for each macrocycle type you are studying.
This will save you time if you are studying many analogues of one particular
macrocycle as you will only need to do the conformational analysis once to
generate the appropriate ring template library.
Please contact admin++ccdc.cam.ac.uk for details on how to obtain
GOLD
Regards
John
-----Original Message-----
> From: owner-chemistry+ccdc-announce==ccdc.cam.ac.uk++ccl.net
[mailto:owner-chemistry+ccdc-announce==ccdc.cam.ac.uk++ccl.net] On Behalf Of
John Furr john.furr/./gmail.com
Sent: 16 June 2010 15:21
To: Rutland, Anne
Subject: CCL: Docking Software for Macrocycles
Sent to CCL by: "John Furr" [john.furr|gmail.com]
Hey gang,
I'm looking for advise/tips about docking software that will work well with
large macrocycles...19+ ring atoms. Software can be commercial or not.
Currently we are using the Schrodinger suite of tools with moderate success.
However our biggest limitation is that glide does not sample large ring
conformations. This means that for every compounds we want to dock we have
to first do an upfront conformational analysis and this takes several hours
to do in a complete manner.
To put it in units of time. It takes me about 4 hours per compound to get a
docked pose for a single CPU. There are literally times that the chemistry
team is faster than me!
Obviously we are very interested in exploring other options that would allow
us to improve our throughput without compromising robustness.
So gang any advise and or tips?
Cheers
John Furrhttp://www.ccl.net/cgi-bin/ccl/send_ccl_messagehttp://www.ccl.net/chemistry/sub_unsub.shtmlhttp://www.ccl.net/spammers.txtLEGAL NOTICE
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From owner-chemistry@ccl.net Thu Jun 17 16:11:00 2010
From: "domenico quartarolo quartarolo[*]unical.it" <owner-chemistry[A]server.ccl.net>
To: CCL
Subject: CCL: TDDFT and B2PLYP
Message-Id: <-42131-100617100308-8962-rOxrzsTLA1ASJJBsICDXwA[A]server.ccl.net>
X-Original-From: "domenico quartarolo" <quartarolo^_^unical.it>
Date: Thu, 17 Jun 2010 10:02:26 -0400
Sent to CCL by: "domenico quartarolo" [quartarolo*unical.it]
I'm using b2plyp for excitation energies calculation as implemented in orca software. For my system the cis(d) correction to b2lyp is of -0.3 eV and the initial excited state excitation energy (b2lyp within Tamm-Dancoff approximation) is 2.4 eV. This last value is greater by about 0.2 eV with respect to the full TD treatment, so the overall effect is that the final excitation energy (with cis(d) correction) does not improve against, say, b3lyp tddft calculation. I would like to know if there is a way to solve this problem with available quantum chemistry packages.
best regards
domenico
quartarolo:-:unical.it
From owner-chemistry@ccl.net Thu Jun 17 17:48:00 2010
From: "Alfredo Tlahuice tlahuicef * fisica.unam.mx" <owner-chemistry---server.ccl.net>
To: CCL
Subject: CCL: About Symmol program use
Message-Id: <-42132-100617113939-26088-hUf/xn1d7Drf0aZ6EbEGzA---server.ccl.net>
X-Original-From: "Alfredo Tlahuice" <tlahuicef]|[fisica.unam.mx>
Date: Thu, 17 Jun 2010 11:38:47 -0400
Sent to CCL by: "Alfredo Tlahuice" [tlahuicef*fisica.unam.mx]
Hi there
Does anybody have the symmol program?
I need to change the puntual group of a molecule from Ih to Th.
Any advice?
Alfredo Tlahuice
From owner-chemistry@ccl.net Thu Jun 17 18:25:00 2010
From: "Josh Szekely j-szekely.]_[.onu.edu" <owner-chemistry]_[server.ccl.net>
To: CCL
Subject: CCL: Qchem aborting unexpectedly
Message-Id: <-42133-100617145647-17087-WHMdOwdiAMMuaDJQp+4Mzg]_[server.ccl.net>
X-Original-From: "Josh Szekely" <j-szekely:-:onu.edu>
Date: Thu, 17 Jun 2010 14:55:53 -0400
Sent to CCL by: "Josh Szekely" [j-szekely,onu.edu]
I am trying to run optimization and frequency calculations on qchem using the SS(V)PE solvation
model with DFT theory. The initial SCF cycle for all of my calculations finishes for the gas phase, but
when the solvation method is applied, the calculation aborts without any sort of error message. I've
tried adjusting memory settings and a few other parameters, but the same thing always happens. Does
anyone have any idea as to what may be causing this issue?
Josh Szekely
j-szekely:-:onu.edu
From owner-chemistry@ccl.net Thu Jun 17 22:06:01 2010
From: "Eric Bennett ericb=-=pobox.com" <owner-chemistry*_*server.ccl.net>
To: CCL
Subject: CCL: Docking Software for Macrocycles
Message-Id: <-42134-100616220742-1425-N3Dax4AJsR7HANpgTvg1Bw*_*server.ccl.net>
X-Original-From: Eric Bennett <ericb..pobox.com>
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Date: Wed, 16 Jun 2010 21:07:06 -0400
MIME-version: 1.0
Sent to CCL by: Eric Bennett [ericb.:.pobox.com]
Since you are already using Glide... If you are making many analogs
of macrocycles often sharing similar cores, the new version of the
Schrodinger suite just released a couple weeks ago has improved
support for user-input ring template data, so once you carry out the
time-consuming up front step of determining the low energy
conformations for your core ring structures subsequent searches
should be much faster. There is a utility to help automate the ring
templating process, and it is described in section 17.8 of the
macromodel manual since the actual template generation is done with
macromodel. I am not sure of all the settings it uses (ie, does it
use LMCS which is probably a good idea in your case) but the default
20,000 search steps might be too small.
>Sent to CCL by: "John Furr" [john.furr|gmail.com]
>Hey gang,
>
>I'm looking for advise/tips about docking software that will work
>well with large macrocycles...19+ ring atoms. Software can be
>commercial or not.
>
>Currently we are using the Schrodinger suite of tools with moderate
>success. However our biggest limitation is that glide does not
>sample large ring conformations. This means that for every
>compounds we want to dock we have to first do an upfront
>conformational analysis and this takes several hours to do in a
>complete manner.
>
>To put it in units of time. It takes me about 4 hours per compound
>to get a docked pose for a single CPU. There are literally times
>that the chemistry team is faster than me!
>
>Obviously we are very interested in exploring other options that
>would allow us to improve our throughput without compromising
>robustness.
>
>So gang any advise and or tips?
>
>Cheers
>John Furr
--
Eric Bennett, ericb(-)pobox.com
We used to quip that "password" is the most common password. Now
it's "password1." Who said users haven't learned anything about
security? -Bruce Schneier