Can anyone clarify, in structure based virtual screening among inhibitor molecules, does minimum binding energy indicates that the docked molecule has shown better binding or better inhibition? If yes then, what does it means if its binding energy decreases when it is combined with substrate molecule?
An inhibitor molecule prevents the substrate from binding to an active pocket and thus inhibits the product formation. Where as in the absence of inhibitor substrate will get converted into product.
Structure based virtual screening can be both receptor/enzyme structure based or ligand structure based (QSAR & pharmacophore).
In Receptor-Ligand interaction, tighter binding means negative binding energy. If some ligand has to be an inhibitor, it should bind better than the substrate. Hope this helps.
it also depends of the software you're using as calculations could slightly vary. Usually you have to refer to the software manual to know the range. Nevertheless, I think it is really difficult to calculate a dissociation constant with such data.
Actually ligand-protein complex with minimum binding energy will be the better confirmation why because, according to thermodynamics, system with minimum binding energy will be more stable.
More the BE lesser the interaction, Lesser the BE more interaction
Binding Energy = [(1) + (2) + (3) - (4)]
Where,
(1) Final Intermolecular Energy,
(2) Final Total Internal Energy,
(3) Torsional Free Energy,
(4) Unbound System's Energy
As Unbound System's Energy is more the binding energy will be less so as the ligand binds the Unbound System's Energy will increase so you can expect minimum BE
Hope helps
@Aditya,
There are some points needed clarification in your question.
Protein inhibition implies binding, whereas binding does not imply inhibition. That is, for a molecule to act as an inhibitor, it must bind to the target, but a molecule binding to the target does not necessarily inhibits the target activity.
An inhibitor blocks product formation, but it does not necessarily hinders substrate binding. There are competitive, non-competitive and un-competitive inhibitors, depending on the cooperativity between substrate and inhibitor. A competitive inhibitor prevents substrate binding, a non-competitive inhibitor may bind with or without the substrate (with different affinity in each case), and an un-competitive inhibitor binds to the enzyme-substrate only.
Therefore, it is posible that a certain inhibitor increases its affinity for the target in the presence of the substrate.
Thank you Dr. Adrian Velazquez-Campoy for your reply and sorry for the inconvenience.. the thing is we isolated an enzyme and studied the effect of few inhibitors acting on the activity of substrate. Based on those results we tried virtual screening studies.
Hi Aditya, Generally we assume that inhibtiors with low binding energies, will be the strong binders, but this is not the truth. There are several factors which influence the ligand binding. Computational prediction of binding energy is still naive area. However for the ranking purpose it is OK. If you are doing virtual screening, then first be sure about the binding site. The binding site should be devoid of any interfering molecules, such as waters or cofactors or substrate, you can only include these, when necessary. If you are searching for compettive inhibitors then substrate should not be present in the active site of receptor.
Please elaborate the statement "inding energy decreases when it is combined with substrate molecule."
Dear Aditya,
I believe you are using Autodock for your docking studies. In principle lesser the binding energy better the affinity, but with docking it becomes difficult to conclude the affinity of ligand only to that site of protein, because you restricted the ligand movement by fixing the grid. Nevertheless, Autodock calculates Ki using,
Ki = exp(deltaG/(R*T))
It is clear that if binding energy increases i.e from -5kcal/mol to say -3 kcal/mol, automatically Ki value also changes from micro to milli molar concentration. In most of the cases AutoDock 4.2 is capable of predicting the right conformation and can consider the least binding energy as best. But one has to see all other conformation once before taking the best becuase of consideration of Hydrogen bonding, vander Waal's forces, hydrophobic interaction etc matters a lot. I prefer to do dynamic simulation once you get promising lead-like molecule in docking for more confidence.
Thank you Prashantha Karunakar Sir,
Yes, I have seen that unit change from micro to milli molar. Thanks for your explanation but related to Hydrogen bonding, i couldn't find the values anywhere in .dlg file. Any idea sir, how it calculates bond length and bond strength...
Sure Vikash Kumar sir, first i would like thank you for your answer. We docked individual molecules fist then we merged .dpf of both molecules and run autodock and the results were extracted form final .dlg file. please find the reference below..
Ok you are using Multiple ligand simultaneous docking(MLSD). Are you getting the docked conformation of both substrate and inhibitors at one time? If two ligands compete for same binding pocket then only one will bind . What is the difference , when you dock singly?
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