Developing predictive models for drug efficacy is challenged by the complexity and heterogeneity of bioassay data. Here, we present LIFE.PTML, which is a methodology integrating drug Lifecycle (L), Information Fusion (IF), Encoding (E), Perturbation Theory (PT), and Machine Learning (ML) to predict compound activity across diverse experimental conditions. Using a dataset of 3748 molecule–assay combinations targeting calmodulin (CaM) and related proteins, LIFE.PTML combines chemical and protein descriptors, quantifies experimental variability via perturbation operators, and trains non-linear classifiers, including XGBoost and Gradient Boosting. XGBoost achieved the best performance, with 88.9% test accuracy and an ROC AUC of 0.959, while feature importance analysis highlighted contributions from both drug- and protein-level descriptors. The results demonstrate that LIFE.PTML provides a robust, flexible, and interpretable framework for predictive chemoinformatics, facilitating the integration of multi-source data for drug discovery applications.