Subject: RE: [ccp4bb]: modeling inhibitor in groove

From: "Teran Castañon, Hugo Gutierrez de"<hteran_at_IMIM.ES>
Date: Tue, 22 Jul 2003 17:24:03 +0200

Hi Peter,

You can overlay the proposed inhibitor to the crystallographic inhibitor on
the basis of molecular electrostatic potential (MEP) or GRID generated
molecular interaction fields (MIF) with the software MIPSIM
(http://www1.imim.es/modeling/mipsim/index.html). With the best
superposition choosen, you can simply replace one inhibitor with the other
one and carry on your simmulations.

Good luck,
Hugo 
-----Original Message-----
From: Peter Zwart
To: Pedro Antonio Reche
Cc: ccp4bb_at_dl.ac.uk; chemistry_at_ccl.net
Sent: 21/07/2003 3:14
Subject: CCL:[ccp4bb]: modeling inhibitor in groove

>
> Hi, I have a PDB of a kinase in complex with a inhibitor, and I would

> like to replace that inhibitor with a related compound. I have 
> already  generated a PDB file for this  compound but I do not  I have 
> to  proceed, and thereby any input about the software (better if unix 
> open  source), and strategy to replace the original inhibitor with 
> this  related compound will be greatly appreciated. Also, does anyone 
> know of  a software to overlay  3D structures of small molecules? I am

> thinking  that overlaying the derivative compound with the inhibitor 
> in the 3D  structure of the kinase would be a possibility, but what 
> software to  use?!
> Anyway,  any idea, or suggestion about best way to solve this problem

> will be greatly appreciated.
> Cheers

You could give MOLREP a try, the manual says:

------------------------------------------------------------------------
-----------------------------------------

      Fitting two models (FM)
      <http://www.yorvic.york.ac.uk/%7Ealexei/molrep.html#FM>

The idea is to fit the electron densities instead of the atomic models, 
trying to find the best overlap. Advantages are:

    * can be used for cases with very low homology;
    * can be used when amino acid sequence is absent;
    * no need to use the list of equivalent atoms.

If you define only two files of models (searching model and model_2), 
without a file of structure factors (Fobs), the program will fit the 
search model (keyword FILE_M 
<http://www.yorvic.york.ac.uk/%7Ealexei/molrep.html#file_m>) to the 
second model (keyword MODEL_2 
<http://www.yorvic.york.ac.uk/%7Ealexei/molrep.html#model_2>). The 
search model must be smaller or equal to the second model.

------------------------------------------------------------------------
-----------------------------------------

No clue how to handle (large) conformational differences though.

Or soak and solve maybe ?

Peter Zwart

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