1/ Theoretically, yes it seems valid but you will be confronted to several issues. 2 main ones could be:

a/ You have to see if the active site is more conserved that the overall protein, don't expect to bind correctly a ligand in a pocket that share a low identity with your template (it also depends on your definition of low identity!).

For example, in a case of Kinase, it is common to have low identity between the kinase (overall of 30-40%) but the ATP binding site, which is very often targeted in drug design, share a much higher identity (70 to 80%).

b/ If your active site identity is not that an issue, you may need rearrangement of the side chain in order to bind correctly the ligand. But Modeller derived homology restraint from the template which doesn't have the ligand (I presume), therefore these restraints may become a problem for your optimization, especially side chain - side chain restraints.

In that case I will suggest you 2 approaches:

- you can delete the side chain - side chain restraints for the active site.

- Build you model without the ligand and dock it after using a docking software.

Now if you template as the same ligand bound into it and you have just some mutation in your active site therefor: Yes you can use your idea.

And to add a small ligand check the FAQs on the manual, you will find some answers.

------------------------------------
Eric Feyfant, Ph.D.
Senior research Scientist
Computational Chemistry
Wyeth Research
200 Cambridge Park Drive
Cambridge, MA 02140
tel: +1 617 665 5656
fax: +1 617 665 5682
email: efeyfant@wyeth.com

>>> Nataraj Balkrishnan <natarajmtech@yahoo.co.uk> 3/29/2004 1:11:10 PM >>>

Dear Modeller,
I modelled a protein from low identies template,and more I am having the idea of location of active site for my modelled protien for particular ligands. Since I know the active site of the model, I want to construct the sidechain of aminoacids involved in that active site,by adding ligand in that particular location.(Since I belive that the configuration of sidechain in the state of interaction with ligand would be the actual conformation of the sidechains of active site).

Now my questions are
1)Wheather my this idea is theoreticaly correct ?

2)if the answer for my question 1 is correct, what is the way or routine which I can use it for adding my ligand(small molecule,eg.,DDT)
to my model?

Kindly help me...
Thank you in advance.

Yours truly,
B.Nataraj

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