I want to study the in-silico docking of a protein to find its potential inhibitors/drugs. Unfortunately I do not have its crystal structure in unbounded form, but I do have its 3D complex structure which is available in DNA and some other proteins bounded state. I am also unable to model its 3D "unbounded or open" structure using homology modeling, as it's showing poor sequence and structure similarity score (I have done the homology modeling). I also know its active site which is available in the literature. Here, I want to find out some drugs or compounds which will block its active or DNA binding site. In this case can I use the bounded structure of that protein for in-silico docking study? If yes, then what is the methodology? If it is possible then please refer any published article or tutorial link (if any).
Thanks
You must use the bounded structure to perform a docking study (as well, you have to remove the natural ligand before docking your compound).
Why do you think that the unbounded form show an open conformation to accomodate the ligands? Usually, the apo forms host a more closed conformation than the holo ones.
You will never obtain experimentally resolved structure in which a transitional empty/open conformation is avalaible. For this reason docking studies use holo forms.
I have heard about docking softwares which evaluate closed conformations to find out putative off-target binding sites. Nevertheless you need a priori knowledge of the endogenous binding site.
Sufficiently long MD simulations could overcome these issues. The transition between "open" and "closed" states is a big challenge, and it simply may not be possible to model these different states. It is clear that ligand binding to many proteins shifts the conformational equilibrium, so it's not really a binary situation. There may not be only one "open" or "closed" state; rather, ensembles of both exist.
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