Modeling of small molecule's affinity to phospholipids using IAM-HPLC and QSRR approach enhanced by similarity-based machine algorithms

•First implementation of locally weighted least squares kernel regression for QSRR.•Highly predictive QSRR model of IAM chromatography.•Lipophilicity, charge, and maximum projection area determine affinity to IAM. Immobilized artificial membrane chromatography (IAM) has been proposed as a more biosimilar alternative to classical lipophilicity measurement. Determination of small molecule's affinity to phospholipids can be supported for predicting their behavior in the human body. Therefore, a better understanding of the molecular interaction mechanism between small xenobiotics and phospholipids can accelerate drug discovery. Here, the quantitative structure-retention relationships (QSRR) approach was integrated with mechanistic descriptors calculated using Chemicalize software to propose an easy-to-interpretation QSRR model. Considering the heterogeneous character of the data set, locally weighted least squares kernel regression belonging to similarity-based machine learning methods have been applied. The results showed that lipophilicity, charge, and maximum projection area determine molecule binding to phospholipids. Full validation of the obtained model based on OECD recommendations has been performed and the applicability domain was defined using the probability-oriented distance-based approach. The high values of predictive squared correlation coefficient (Q2), and small root mean square error of prediction (RMSEP), 0.812 and 6.739, respectively, confirmed that the obtained QSRR model is not well-fitted to the training data but also showed prediction power. Additionally, only 1.5% of molecules from the training set and 2.8% from the validation test are outside the applicability domain, confirming great predictive abilities.