For bifunctional molecule whether i prefer metal binding site for docking or directly go to the best interaction site for drug on protein.
Manoj,
Better get away from the metal binding site. There are several enzymes in a cell with metals. Several time there is a cross of inhibitors with different metallo enzymes.
Respected Sir,
Main objective of my experiment is to remove the metal ions, as the metals ion are responsible for amyloid aggregation which is one of the cause of AD. So in that case whether I go for site where metals are mostly found or just any site on protein where compound show more interaction.
Manoj,
The purpose is simple. You want to obstruct the enzyme function. If there is a site that is important for your enzyme function other than metal binding reagion then terget it. Otherwise you have no choice. You cannot choose any pocket in the enzyme as a site of docking unless it is known to be important for the enzyme function.
Thank you, sir for your kind attention in this matter. I notice all the points you mentioned.
thank you
You may want to look at these studies:
https://www.researchgate.net/publication/265300213_Interaction_and_reactivity_of_synthetic_aminoisoflavones_with_metal-free_and_metal-associated_amyloid-
https://www.researchgate.net/publication/259626002_Rational_design_of_a_structural_framework_with_potential_use_to_develop_chemical_reagents_that_target_and_modulate_multiple_facets_of_Alzheimer%27s_disease
https://www.researchgate.net/publication/235682218_Insights_into_antiamyloidogenic_properties_of_the_green_tea_extract_%28-%29-epigallocatechin-3-gallate_toward_metal-associated_amyloid-_species
Article Synthetic Flavonoids, Aminoisoflavones: Interaction and Reac...
Article Rational Design of a Structural Framework with Potential Use...
Article Insights into antiamyloidogenic properties of the green tea ...
Manoj:
There are many ways to determine the best possible binding site. It will depend on which type of amyloid structure you want to use. Monomer, dimer, oligomers/fibrils. Steric zipper assembly is a quick method to determine if your compounds can bind in the KLVFFA region of beta amyloid (http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1001080). My suggestion would be to try all the possible sites and calculate ligand-complex energy or binding energy to determine the most stable location.
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