Alchemical free energy calculations have come of age. Based on rigorous first principles of statistical mechanics, these calculations explore physical paths not experimentally accessible and provide unprecedented accuracy in the prediction of processes as diverse as protein thermostability and ligand binding free energies. In the talk I will cover the latest developments in pmx focusing on the protein-ligand binding affinity calculations. I will present the results from the large scale relative and absolute binding free energy calculations. I will also discuss efficiency and performance-to-price ratio of such simulations when run in an HPC center and in the cloud infrastructure.