RE: QSAR - Cation-Pi interactions

Dr. Jones,
 
I agree with Dr. Goldblum. You are trying to characterize an ion-pi
cloud interaction which can occur at some distance even beyond charge
transfer complexes. In my opinion, charge transfer complexes (a type of
induction interaction between aromatic rings whereby a static donation
of charge density and deficiency form a bond may occur between say 3.5
and 5 angstroms) cannot be wholly and adequately treated by a single
technology. Even at the quantum level, the distances are too great (the
size of the basis sets normally used can approximate 1 to 2 angstroms)
but accuracy decays rapidly beyond the covalent radius.
 
One possibility is to perform molecular docking at the at the mechanics
level, and than individually characterize the electronic dispositions of
the ligands with a quantum treatment. We have used this approach with
DFT in a similar manner to rationally design CDK inhibitors (see
Anticancer Drug Des. 2000 Feb;15(1):53-66).
 
Another possibility is to utilize the hybrid approach such as the one
presented paper: Salomon R. Billeter, Simon P. Webb, Tzvetelin Iordinov,
Pratul K. Agarwal and Sharon Hammes-Schiffer. "Hybrid Approach for
Including Electronic and Nuclear Quantum Effects in Molecular Dynamics
Simulations of Hydrogen Transfer Reactions in Enzymes."
<http://ojps.aip.org/jcpo/top.jsp> Journal of Chemical Physics. Volume
14 (
<http://www-fbsc.ncifcrf.gov/publications/pub_rpt_upd.php?atr_nmAll=all&
yr_sortby=2001> 2001): 6925-6936.
 
By the way, I was thinking about doing some neurological diagnoses in my
spare time. What neurodiagnostic techniques and tools do you recommend I
learn/use? Just kidding.
 
Good luck,
 
Rick Gussio
 
 
 
====================================================================
Rick Gussio, Ph.D. (Lieutenant Commander, USPHS)
Target Structure Based Drug Discovery Group
Information Technology Branch, Developmental Therapeutics Program
National Cancer Institute
P.O. Box B, Suite 310, Fairview Center, Frederick, Maryland 21702
E-mail: gussio- -ncifcrf.gov Phone: 301-846-5791 Fax: 301-846-6106
====================================================================
 
 
-----Original Message-----
From: qsar_society-admin{}accelrys.com
[mailto:qsar_society-admin_._accelrys.com] On Behalf Of Amiram Goldblum
Sent: Monday, August 02, 2004 3:51 PM
To: qsar_society~~accelrys.com
Subject: Re: QSAR - Cation-Pi interactions
 
Dear Dr. Jones,

If you are using Molecular mechanics with MM (molecular mechanics)
force fields, there are no electrons involved and you can not
learn anything about orbital energies. Those can only be studied
by Quantum mechanics approaches. The issue of using semiempirical
vs. ab initio (and there are many options in each of them)
should primarily be determined by the "resolution" of the
experiments that you wish to compare to. I suspect that if
you wish to compare to biological results, try first some
semiempirical QM method such as those that may be found
in the MOPAC packages (AM1, PM3 etc..). You could
later try a QM/MM approach if you need to look at larger systems.

Good luck,

Amiram Goldblum
At 03:28 02/08/2004, you wrote:

NB: Unless you reset the To: line, your reply goes to the entire list

---
Please help a novice.  I am a neurologist who is trying to
learn to use computational chemistry for certain
applications in understanding drug action.  I have been
experimenting with molecular dynamics to study the effects
of cations on the orbital energies of aromatic systems in
small molecules.  Is this a valid approach?  Is there a
superior approach?  Are semi-empirical or ab initio, or DFT
methods capable/better for handling such "non-bonded"
interactions?
Sincerely,
GLJones, MD
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Amiram Goldblum, Ph.D. Cell: 972-54-653292 
Professor of Medicinal Chemistry Tel: 972-2-6758701 
Molecular Modeling and Drug Design Fax: 972-2-6758925 
Department of Medicinal Chemistry and Natural Products 
School of Pharmacy, Hebrew University of Jerusalem 
ISRAEL 91120 email: amiram%%vms.huji.ac.il 
Internet: http://www.md.huji.ac.il/models/ 
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