Can I computationally predict whether my ligand is an activator or inhibitor to the enzyme?
I think that do not exist a simple answer to your question, but a mix of docking and QSAR may be usefull
@ all
docking predict free binding energy that can be used in several ways to predict the affinity (Ki) , but how to detect whether this binding will cause activation or inhibition of the enzyme?
If a set of known activators and inhibitors and activators exist, the best strategy may be to ignore the protein and look for chemical similarities and differences within the inhibitor and activator sets using an abstract representation of each molecule. This type of procedure is known to be very good (generally more accurate than docking) for screening databases for biologically active compounds once one active is known.
http://www.daylight.com/dayhtml/doc/theory/theory.finger.html
This can be done in the free program OpenBabel by the commands
babel query.sdf known_actives.sdf -ofpt
babel query.sdf known_inhibitors.sdf -ofpt
this will give the chemical similarity between the molecule you want (query.sdf) and each molecule in the set of either known actives or inhibitors. A high number of matches between one set and not the other will likely tell you which class it falls into.
This can be made more quantitative by constructing what is known as a ligand profile which is a representation of how often each chemical feature appears in the set. However, I am not not sure if this can be done directly with standard off the shelf programs.
Use this tools :http://bioinfo3d.cs.tau.ac.il/PatchDock/index.html and select the option enzyme-inhibitor
Good luck!!!
The enzyme inhibitor option on patchdock will not distinguish allosteric activators from inhibitors. It is just used to change the parameters for small molecule and antibody-antigen vs other types
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1160241/?tool=pubmed
@ Jorge
I think this is a protein-protein docking server not a protein-ligand
patchdock will do small molecule protein docking. However, it will not distinguish inhibitors and activators
Zinc Database
35 million purchasable compounds
http://zinc.docking.org/search/
Chembl
search known ligands by target 1.3 million compounds
https://www.ebi.ac.uk/chembl/target/browser
these sites doesn't contain (PDB) file for chemicals ...only for proteins.
the server doesn't accept MOL files ... it enquires PDB file
It depends on whether the ligand you are referring to is the natural (wild-type) substrate of the enzyme, a variant substrate, the natural cofactor, or a variant cofactor. If the ligand is the WT substrate, then it does not make sense to say whether it activates or inhibits the enzyme, because it will be turned over by the enzyme in the regular fashion. If it is a variant substrate, it may activate or inhibit the enzyme depending on whether it functions as an agonist or as an antagonist (respectively) for the enzyme. Similarly in the case of a cofactor. The key is to carefully analyze the interactions between the ligand atoms and the residues lining the enzyme's active site (AS). One key is the affinity constant of the enzyme with the ligand: if too small, the binding will be too tight, and the ligand most likely will be inhibitory. For example, if there are way too many H-bonds and/or VDW interactions between ligand and the enzyme's AS compared to the wild-type case, you can expect inhibition. If the interactions in the As are too few, the ligand may not even bind to the enzyme. In order to computationally predict inhibition or activation, you can write a computer program to automate the steps in analyzing the interactions between the ligand and the enzyme AS (or search the internet for a program that is already written). I hope this makes sense. HTH.
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