QPhAR – Quantitative Pharmacophore Activity Relationship: Method and Validation

Abstract

QSAR methods are widely applied in the drug discovery process, both in the hit‑to‑lead and lead optimization phase, as well as in the drug-approval process. Most QSAR algorithms are limited to using molecules as input and disregard pharmacophores or pharmacophoric features entirely. However, due to the high level of abstraction, pharmacophore representations provide some advantageous properties for building quantitative SAR models. The abstract depiction of molecular interactions avoids a bias towards overrepresented functional groups in small datasets. Furthermore, a well‑crafted quantitative pharmacophore model can generalise to underrepresented or even missing molecular features in the training set by using pharmacophoric interaction patterns only. This paper presents a novel method to construct quantitative pharmacophore models and demonstrates its applicability and robustness on more than 250 diverse datasets. 5‑fold cross-validation on these datasets with default settings yielded an average RMSE of 0.62, with an average standard deviation of 0.18. Additional cross-validation studies on datasets with 15-20 training samples showed that robust quantitative pharmacophore models could be obtained. These low requirements for dataset sizes renders quantitative pharmacophores a viable go-to method for medicinal chemists, especially in the lead-optimisation stage of drug discovery projects.