Small molecule design puzzles present a protein and a small molecule or ligand. Unlike other Foldit design puzzles, changes to the protein are limited, but a new set of tools is available for changing the small molecule.
Small molecule design was originally referred to as "drug design", since one application would be designing drugs to target proteins associated with diseases.
Small molecule design has been in development for several years in Foldit, but has been held back by technical challenges. Puzzle 1432: HIV Protease Inhibitor Small Molecule Design was the first successful small molecule design puzzle.
In the original interface, there are three new modes available for small molecule design puzzles: Ligand Design, Ligand View, and Reaction Design. In the selection interface, the equivalent tools become available when the small molecule is selected.
The use of "ligand" in may be subject to change. Some of the tools have "ligand" in the button which selects the tool, but then show "small molecule" in the title of the tools dialog window.
In both interfaces, the ligand design feature depends on selecting one or more atoms of the small molecule or ligand. Although this is somewhat similar to selecting segments in the selection interface, the logic is different. Clicking on an atom in the ligand highlights the atom. Additional atoms become selected as you click on them. Control-clicking clears the selected atoms, as does the "broom" icon in the small molecule design window.
The X-ray tunnel for ligand feature may be helpful in revealing the small molecule when it's surrounded by protein.