Machine learning classifiers trained on class imbalanced data are prone to overpredict the majority class. This leads to a larger misclassification rate for the minority class, which in many real-world applications is the class of interest. For binary data, the classification threshold is set by default to 0.5 which, however, is often not ideal for imbalanced data. Adjusting the decision threshold is a good strategy to deal with the class imbalance problem. In this work, we present two different automated procedures for the selection of the optimal decision threshold for imbalanced classification. A major advantage of our procedures is that they do not require retraining of the machine learning models or resampling of the training data. The first approach is specific for random forest (RF), while the second approach, named GHOST, can be potentially applied to any machine learning classifier. We tested these procedures on 138 public drug discovery data sets containing structure-activity data for a variety of pharmaceutical targets. We show that both thresholding methods improve significantly the performance of RF. We tested the use of GHOST with four different classifiers in combination with two molecular descriptors, and we found that most classifiers benefit from threshold optimization. GHOST also outperformed other strategies, including random undersampling and conformal prediction. Finally, we show that our thresholding procedures can be effectively applied to real-world drug discovery projects, where the imbalance and characteristics of the data vary greatly between the training and test sets.