On the other hand, free energy methods are much more computationally expensive approaches to molecular design that employ rigorous thermodynamics and carefully parameterised force fields to compute (relative or absolute) protein-ligand binding free energies. As such, they overcome many of the accuracy limitations of de novo design workflows, and are commonly employed in prospective design efforts to explore and prioritise relatively small perturbations in the hit-to-lead stage. Many excellent tutorials and best practice documentation are available, but most start from the assumption that the user has already built initial poses of the ligands in the binding pocket. For simple R-group additions, input coordinates may be built from maximum common substructure alignment, for example, but it may be difficult to resolve steric clashes or decide between two alternative 3D poses in more complicated cases. Some widely-used graphical user interfaces, such as Maestro and Chimera, are also available for building R-groups, but these can be proprietary and/or difficult to build into automated workflows and modify according to user needs.