Critically Assessing the Predictive Power of QSAR Models for Human Liver Microsomal Stability

J Chem Inf Model. 2015 Aug 24;55(8):1566-75. doi: 10.1021/acs.jcim.5b00255. Epub 2015 Jul 29.


To lower the possibility of late-stage failures in the drug development process, an up-front assessment of absorption, distribution, metabolism, elimination, and toxicity is commonly implemented through a battery of in silico and in vitro assays. As in vitro data is accumulated, in silico quantitative structure-activity relationship (QSAR) models can be trained and used to assess compounds even before they are synthesized. Even though it is generally recognized that QSAR model performance deteriorates over time, rigorous independent studies of model performance deterioration is typically hindered by the lack of publicly available large data sets of structurally diverse compounds. Here, we investigated predictive properties of QSAR models derived from an assembly of publicly available human liver microsomal (HLM) stability data using variable nearest neighbor (v-NN) and random forest (RF) methods. In particular, we evaluated the degree of time-dependent model performance deterioration. Our results show that when evaluated by 10-fold cross-validation with all available HLM data randomly distributed among 10 equal-sized validation groups, we achieved high-quality model performance from both machine-learning methods. However, when we developed HLM models based on when the data appeared and tried to predict data published later, we found that neither method produced predictive models and that their applicability was dramatically reduced. On the other hand, when a small percentage of randomly selected compounds from data published later were included in the training set, performance of both machine-learning methods improved significantly. The implication is that 1) QSAR model quality should be analyzed in a time-dependent manner to assess their true predictive power and 2) it is imperative to retrain models with any up-to-date experimental data to ensure maximum applicability.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms
  • Computer Simulation
  • Databases, Pharmaceutical
  • Drug Discovery / methods*
  • Drug Stability
  • Humans
  • Machine Learning
  • Microsomes, Liver / metabolism*
  • Models, Biological
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Quantitative Structure-Activity Relationship*


  • Pharmaceutical Preparations