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

From: Peter Zwart <Zwart_at_embl-hamburg.de>
Date: Mon, 21 Jul 2003 03:14:33 +0200

>
> 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:

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      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.

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

Or soak and solve maybe ?

Peter Zwart

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