We use molecular docking and free energy calculations to estimate the relative free energy of binding of six arylamide compounds designed to inhibit the hDM2-p53 interaction. We show that using docking methods to predict or rank the binding affinity of a series of arylamide inhibitors of the hDM2-p53 interaction is problematic. However, using free energy calculations, we show that we can achieve levels of accuracy that can guide the development of novel arylamide compounds. We perform alchemical free energy calculations using the Desmond molecular dynamics package with the same arylamide inhibitors of the hDM2-p53 system and illustrate the challenges of performing accurate free energy calculations for realistic systems. To our knowledge, these are the first calculations for inhibitors of the hDM2 system that employ a full treatment of statistical mechanics including explicit water representation and full protein flexibility. We show that mutating three functional groups in a single transformation can be more efficient than mutating the groups one by one if proper intermediates are used. We also show that Hamiltonian exchanges can improve the efficiency of the calculation compared to standard alchemical methods, with a novel use of the phase space overlap to monitor sampling extent. We show that, despite sampling limitations, this approach can achieve levels of accuracy sufficient to bias further inhibitor modification toward binding, and identifies antiparallel configurations as stable or more stable than the parallel configurations that are typically considered.