[Users-list] metasite/grid

[Gabriele Cruciani]

OK I understand now.
However (I'm sorry) but I think MetaSite cannot help you so much.
Basic assumption of MetaSIte is the possibility for the ligand to reach 
the heme
without making strong interactions in other part of the CYP.
Have you tried normal docking procedures?
Gabry

Lewis, Ben (FMC) ha scritto:

>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/
>The contents of this email are intended only for the named recipient and
>may be confidential. If you have received this communication in error,
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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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