The successful application of high throughput molecular simulations to determine biochemical properties would be of great importance to the biomedical community if such simulations could be turned around in a clinically relevant timescale. An important example is the determination of antiretroviral inhibitor efficacy against varying strains of HIV through calculation of drug-protein binding affinities. We describe the Binding Affinity Calculator (BAC), a tool for the automated calculation of HIV-1 protease-ligand binding affinities. The tool employs fully atomistic molecular simulations alongside the well established molecular mechanics Poisson-Boltzmann solvent accessible surface area (MMPBSA) free energy methodology to enable the calculation of the binding free energy of several ligand-protease complexes, including all nine FDA approved inhibitors of HIV-1 protease and seven of the natural substrates cleaved by the protease. This enables the efficacy of these inhibitors to be ranked across several mutant strains of the protease relative to the wildtype. BAC is a tool that utilizes the power provided by a computational grid to automate all of the stages required to compute free energies of binding: model preparation, equilibration, simulation, postprocessing, and data-marshaling around the generally widely distributed compute resources utilized. Such automation enables the molecular dynamics methodology to be used in a high throughput manner not achievable by manual methods. This paper describes the architecture and workflow management of BAC and the function of each of its components. Given adequate compute resources, BAC can yield quantitative information regarding drug resistance at the molecular level within 96 h. Such a timescale is of direct clinical relevance and can assist in decision support for the assessment of patient-specific optimal drug treatment and the subsequent response to therapy for any given genotype.