Notable successful computer-aided design efforts have used free energy calculations in conjunction with de novo design tools to build (and maybe score) new molecules. Jorgensen and co-workers have pioneered this approach for many years, linking de novo design through the biochemical and organic model builder (BOMB) software with free energy perturbation (FEP) through the MCPRO software. BOMB builds ligands into a binding pocket by linking user-defined R-groups to an existing core. Functionality is available for conformer searching, structural optimisation and scoring, using a custom scoring function trained via linear regression on > 300 experimental activity data points. Once hits have been built and scored, hit-to-lead optimisation may be further refined through free energy calculations. Such an approach has yielded extremely potent series of leads against HIV reverse transcriptase, macrophage migration inhibitory factor and the SARS-CoV-2 main protease. In other drug discovery programmes, as part of the recent COVID Moonshot open science effort to crowd source design of SARS-CoV-2 main protease inhibitors, the Omega toolkit by OpenEye 26 is used for constrained conformer generation, and optimal binding poses are then taken through to free energy calculations using the perses software. The evident importance of input structure to the reliability of free energy calculations means that open-source tools to automate this step are crucial.