Rationalizing general limitations in assessing and comparing methods for compound potency prediction

Abstract

Compound potency predictions play a major role in computational drug discovery. Predictive methods are typically evaluated and compared in benchmark calculations that are widely applied. Previous studies have revealed intrinsic limitations of potency prediction benchmarks including very similar performance of increasingly complex machine learning methods and simple controls and narrow error margins separating machine learning from randomized predictions. However, origins of these limitations are currently unknown. We have carried out an in-depth analysis of potential reasons leading to artificial outcomes of potency predictions using different methods. Potency predictions on activity classes typically used in benchmark settings were found to be determined by compounds with intermediate potency close to median values of the compound data sets. The potency of these compounds was consistently predicted with high accuracy, without the need for learning, which dominated the results of benchmark calculations, regardless of the activity classes used. Taken together, our findings provide a clear rationale for general limitations of compound potency benchmark predictions and a basis for the design of alternative test systems for methodological comparisons.