[Users-list] metasite/grid

[Lewis, Ben (FMC)]

Gabry,
The project I am undertaking involves gene therapy with a CYP not
expressed in the liver but in limited amounts in other regions of the
body. This particular CYP activates a prodrug which has potential for a
cytotoxic. Trouble is that the kinetics for the drug is not great (km
600uM). Mutagenesis may enhance activation of the prodrug. If this
occurs, a promoter activated by a cofactor present in cancer cells could
be used to localize chemotherapy, thus limiting toxic side effects.

I have generated a homology model and docked my substrate. The catalytic
site is some 5A from the heme Fe. What I thought was to mutate residues
in the active site and re-dock the substrate to try and give me
information about orientation of the substrates catalytic site above the
heme Fe. I guess I was hoping metasite could help in refining the site
of oxidation in those ligands docked into mutant proteins.

Perhaps you know of some other software capable of optimizing the active
pocket about a substrate.
Thank you for your reply. I wish you a merry Christmas and a jubilant
new year.

Kind regards,

Benjamin Lewis BSc (Hons) MRACI
Chartered Chemist
 
Research Associate/PhD candidate
Department of Clinical Pharmacology,
School Of Medicine,
Flinders University
Bedford Park
South Australia 5042
Australia
 
T +61 88204 4795
F +61 88204 5114
E ben.lewis at fmc.sa.gov.au
W http://som.flinders.edu.au/FUSA/ClinPharm/
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-----Original Message-----
From: users-list-bounces at moldiscovery.com
[mailto:users-list-bounces at moldiscovery.com] On Behalf Of Gabriele
Cruciani
Sent: Monday, 19 December 2005 18:14
To: Support and general discussions
Subject: Re: [Users-list] metasite/grid

Ben
I do not think it make any (pragmatic) sense.
We will not be able to change our CYP enzyme (in our body) anyway.
Probably you suggested that to 'understand'  the role of particular 
aminoacid
in the CYP structure(s). However, CYPs are promiscuous enzymes,
and the in silico site direct mutagenesis approach, at least here, will
not
work (in my opinion).

Nice Christmas
Gabry

Lewis, Ben (FMC) ha scritto:

>Yes that's correct Gabry.
>
>Benjamin Lewis BSc (Hons) MRACI
>Chartered Chemist
> 
>Research Associate/PhD candidate
>Department of Clinical Pharmacology,
>School Of Medicine,
>Flinders University
>Bedford Park
>South Australia 5042
>Australia
> 
>T +61 88204 4795
>F +61 88204 5114
>E ben.lewis at fmc.sa.gov.au
>W http://som.flinders.edu.au/FUSA/ClinPharm/
>The contents of this email are intended only for the named recipient
and
>may be confidential. If you have received this communication in error,
>please contact us then delete the email and any attachments. You must
>not copy, distribute or disclose this message or any part of it to
>anyone.
>
>-----Original Message-----
>From: users-list-bounces at moldiscovery.com
>[mailto:users-list-bounces at moldiscovery.com] On Behalf Of Gabriele
>Cruciani
>Sent: Saturday, 17 December 2005 01:10
>To: Support and general discussions
>Subject: Re: [Users-list] metasite/grid
>
>Hi Ben ...
>do you mean CYP Protein residues?
>Gabry
>
>
>Lewis, Ben (FMC) ha scritto:
>
>  
>
>>Firstly, hi to all subscribers of this list; I have just joined up...
>>
>>Question:
>>
>>I was wondering if anyone uses MetaSite or Grid to determine what 
>>residues to mutate to get better turnover of a drugs metabolism?
>>
>>Kind regards,
>>
>>**Benjamin Lewis BSc (Hons) MRACI**
>>
>>//Chartered Chemist//
>>
>>Research Associate/PhD candidate
>>
>>Department of Clinical Pharmacology,
>>
>>School Of Medicine,
>>
>>Flinders University
>>
>>Bedford Park
>>
>>South Australia 5042
>>
>>Australia
>>
>>//T//** **+61 88204 4795
>>
>>//F// +61 88204 5114
>>
>>//E// ben.lewis at fmc.sa.gov.au <mailto:ben.lewis at fmc.sa.gov.au>
>>
>>//W// http://som.flinders.edu.au/FUSA/ClinPharm/
>>
>>/The contents of this email are intended only for the named recipient 
>>and may be confidential. If you have received this communication in 
>>error, please contact us then delete the email and any attachments. 
>>You must not copy, distribute or disclose this message or any part of 
>>it to anyone/.
>>
>>----------------------------------------------------------------------
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>>    
>>
>-
>  
>
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