Efficient R-group exploration in the vast chemical space, enabled by increasingly available building blocks or generative AI, remains an open challenge. Here, we developed an enhanced Free-Wilson QSAR model embedding R-groups by atom-centric pharmacophoric features. Regioisomers of R-groups can be distinguished by explicitly accounting for the atomic positions. Good predictivity is observed consistently across 12 public data sets. Integrated into an open-source program, we showcase its application in performing Free-Wilson analysis as well as R-group exploration in an uncharted chemical space.