The confidence on the ΔΔGQB predictions can be evaluated a priori with a simple heuristic. Considering what has been observed in the other systems, we suggest the following two-step protocol to evaluate the applicability of ΔGQB to predict activity cliffs: Firstly, systems with a robust main interaction (high ΔGQB values) have shown better performance in the activity cliff prediction (i.e., HSP90α and CDK2 series B) than labile ones. Thus, one should test representative compounds and proceed only if they reach high ΔGQB values (e.g. >15 kcal mol -1