Computer-aided approaches to ligand design need to balance accuracy with speed. This is particularly true for one of the key parameters to be optimized during ligand development, the free energy of binding (\documentclass[12pt]{minimal}
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				\begin{document}$$_{\text {bind}}$$\end{document}bind). Here, we developed simple models based on the Linear Interaction Energy approximation to free energy calculation for a G protein-coupled receptor, the serotonin receptor 2A, and critically evaluated their accuracy. Several lessons can be taken from our calculations, providing information on the influence of the docking software used, the conformational state of the receptor, the cocrystallized ligand, and its comparability to the training/test ligands.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10822-023-00507-3.