Binding free energy (ΔG bind ) computation can play an important role in prioritizing compounds to be evaluated experimentally on their affinity for target proteins, yet fast and accurate ΔG bind calculation remains an elusive task. In this study, we compare the performance of two popular end-point methods, i.e., linear interaction energy (LIE) and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA), with respect to their ability to correlate calculated binding affinities of 27 thieno[3,2-d]pyrimidine-6-carboxamide-derived sirtuin 1 (SIRT1) inhibitors with experimental data. Compared with the standard single-trajectory setup of MM/PBSA, our study elucidates that LIE allows to obtain direct ("absolute") values for SIRT1 binding free energies with lower compute requirements, while the accuracy in calculating relative values for ΔG bind is comparable (Pearson's r = 0.72 and 0.64 for LIE and MM/PBSA, respectively). We also investigate the potential of combining multiple docking poses in iterative LIE models and find that Boltzmann-like weighting of outcomes of simulations starting from different poses can retrieve appropriate binding orientations. In addition, we find that in this particular case study the LIE and MM/PBSA models can be optimized by neglecting the contributions from electrostatic and polar interactions to the ΔG bind calculations.