I performed a molecular docking on inhibitor namely for example compound A, B and C. Results from the binding energies and Ki from docking show that the potency increased in the order of B>A>C.
However, when conducting kinetic study to measure inhibition constant. I obtained unmatching pattern, in this case the potency of the compounds in the order of B>C>A?
What are the possible factors to influence the results?
https://en.wikipedia.org/wiki/Binding_constant
Binding energies are thermodynamic, related to binding equilibrium constants https://en.wikipedia.org/wiki/Binding_constant. At equilibrium, the binding constant is the ratio between the kinetic rates of binding and dissociation, kon and koff. For similar ligands, on-rates are fairly similar, and differences in the equilibrium constant Kd are mainly governed by differences in the off-rate. However, if binding requires conformational changes/ a specific conformation of either ligand or receptor, this can affect the on-rate.
Hi,
in addition to Annemarie Honegger response, it will be very unlikely to obtain such information from docking, because it will also depend on the search and scoring algorithms from your chosen docking software.
Probably through MD you would be able to get more accurate matches.
Docking scores rarely correlate with experimental pIC50. It is easier to reproduce binding mode than to predict binding free energy; the latter requires, besides sampling of the conformational space, a rigorous treatment of solvent effects and long-range electrostatic interactions -- and this is computationally expensive. And the purpose of docking is obviously to obtain answers quickly, hence the trade-off.
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