QSAR Development for Plasma Protein Binding: Influence of the Ionization State

PurposeThis study explored several strategies to improve the performance of literature QSAR models for plasma protein binding (PPB), such as a suitable endpoint transformation, a correct representation of chemicals, more consistency in the dataset, and a reliable definition of the applicability domain.MethodsWe retrieved human fraction unbound (Fu) data for 670 compounds from the literature and carefully checked them for consistency. Descriptors were calculated taking account of the ionization state of molecules at physiological pH (7.4), in order to better estimate the affinity of molecules to blood proteins. We used different algorithms and chemical descriptors to explore the most suitable strategy for modeling the endpoint. SMILES (simplified molecular input line entry system)-based string descriptors were also tested with the CORAL software (CORelation And Logic). We did an outlier analysis to establish the models to use (or not to use) in case of well recognized families.ResultsInternal validation of the selected models returned Q(2) values close to 0.60. External validation also gave r(2) values always greater than 0.60. The CORAL descriptor based model for fu was the best, with r(2) 0.74 in external validation.ConclusionsPerformance in prediction confirmed the robustness of all the derived models and their suitability for real-life purposes, i.e. screening chemicals for their ADMET profiling. Optimization of descriptors can be useful in order to obtain the correct results with a ionized molecule.