pIC50 Affinity Prediction Output Question

[bwhall61]

Hi, super cool model - I'm really excited to try it out. I was just wondering if it would be possible to clarify what the affinity output is actually predicting.

Typically pIC50 is defined as $\mathrm{pIC}_{50} = -\log{10} (IC50)$ where the IC50 is given in M, such that a molecule with an IC50 of 1uM (10^-6 M) would have a pIC50 of 6 and a molecule with an IC50 of 0.1uM would have a pIC50 of 7.

But the wording in the documentation makes it sound like this isn't the case for the model output and that smaller outputs are predicted better binders, which is the opposite of typical pIC50s. Is the equation you guys are using: $\mathrm{pIC}_{50} = +\log{10} (IC50)$ where IC50 is given in uM? So a molecule with an IC50 of 1uM would have a model output of 0, an IC50 of 0.1uM would have a model output of -1 and an IC50 pf 10uM would have a model output of 1?

Sorry if this is covered somewhere, I was just getting confused.

Thanks!

[jbderoo]

In their slack channel, they confirmed that the predicted affinity values are –log10(IC50 in μM). Hope this helps!

[Saro00]

Sorry for the confusion! I am updating the prediction.md to make it more clear! We predict log10(IC50 in μM) which is equivalent as log10(IC50 in M) + 6 .

A few examples:

• IC50 of $10^{-9}$ M $\rightarrow$ our model outputs -3 (strong binder)
• IC50 of $10^{-6}$ M $\rightarrow$ our model outputs 0 (moderate binder)
• IC50 of $10^{-4}$ M $\rightarrow$ our model outputs 2 (weak binder / decoy)

You can convert the model's output to pIC50 in kcal/mol by using:

y --> (6 - y) * 1.364

where y is the model's prediction.

[rjrich]

I agree that the way affinity is described is confusing. I am accustomed to expressing affinity as pIC50 = -log(IC50). Alternatively, affinity can be expressed as a dissociation constant, Kd, which can be converted to an apparent free energy of binding by the following relationship: ΔG = -RT ln(Kd), where ΔG = change in Gibbs free energy; R = ideal gas constant; and T = absolute temperature in Kelvin.

[bwhall61]

prediction.

Thank you for the clarification!

[rjrich]

Is it valid to convert a pIC50 value to a "binding energy" or apparent "free energy of binding"? The conversion that is more typically seen is converting Kd to ΔG. However, the IC50 or pIC50 is not equivalent to the Kd, although these values can be close to each other under some conditions.