I have two compounds first one i.e.CompA having IC50 of about 11uM and another one i.e. CompB with IC50 greater than 100 uM resulting in CompA as active compound and CompB as inactive compound. I calculated Binding Free Energy using MMGBSA and entropy using Quasi-harmonic Approximation
for CompA : binding free energy -29.7526 kcal/mole without entropy and -6.2170 with entropy.
CompB : binding free energy was -24.5334 kcal/mole without entropy and -2.7336 with entropy.
Also in some papers I see that entropy is not included and yet the comparison is done. When and under what circumstances should one include or exclude entropy
In an AMBER tutorial, http://ambermd.org/tutorials/advanced/tutorial3/
It is stated that "in practice entropy contributions can be neglected if only a comparison of states of similar entropy is desired such as two ligands binding to the same protein. The reason for this is that normal mode analysis calculations are computationally expensive and tend to have a large margin of error that introduces significant uncertainty in the result."
I guess it would be a similar situation if you are using programs other than AMBER.
@radu Thanks for the reply
Do you mean that even a ligand with high IC50 value can have negative binding affinity and it in always negative even if ligand is poor binder?
@yun shi thanks for the reply
i am using AMBER and hence your reply is relevant to me.
what if same ligand is docked to wild type and mutant type strains OR different ligand is docked to wild type and mutant type strains?
Yess .. It can have. I think there is no direct correlation of Binding energy with activity (say IC50). Only relative binding energies are important. Not the absolute values.
Do you know if compound B actually binds or is 100 uM the upper limit if the assay? A 100 uM ligand, whole not potent, is still a binder.
By definition if a compound binds to a protein it has a negative (favorable) binding free energy. Even with very low affinity (millimolar IC50 or Kd) the binding free energy will be negative, just small.
Docking results cannot, by their nature, ever predict binding affinity, and while MD could predict binding affinity the errors are so large as to make the predictions very difficult to use prospectively.
@Sudheer - there should be a correlation between binding energy/binding affinity and IC50, but it may be weak. Binding affinity, which is exactly calculable from binding energy and vice-versa, is not the same as IC50, as IC50 measures the effect of a ligand on inhibiting the catalytic activity of a system, which is not the same as intrinsic binding affinity to a protein.
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