12 This increases the computational cost, which can be prohibitive for a large compound series. A rapid alternative to this method would be highly desirable, particularly in the hit-to-lead and early optimization stages of drug discovery, where thousands of analogs may need to be considered. Even if less accurate, it would be highly useful for drug design to predict activity cliffs (ACs; i.e., changes in Kd larger than 100-fold, corresponding to a ΔΔGbind > 2.73 kcal mol -1