Figure 4.

FRAME successfully expands small starting ligands by adding multiple fragments, as desired in fragment-based drug design. Reference ligands (green sticks) and pockets (gray surface) for three example proteins from the test set are shown in the left column. A small starting molecule was randomly selected from the reference ligand to initiate expansion; the starting molecule is shown in green in the middle and right columns. The starting molecules were expanded using FRAME to select attachment points and fragments; the resulting molecules are shown in the middle column (added fragments shown in purple). We compared these to molecules generated using iterative docking (with Glide) to select fragments, right column. A single expanded molecule (the one shown in each image) was generated per pocket for each method. Key interactions are highlighted by circles and dotted lines: hydrogen bonds in red, π–π interactions in blue, and salt bridges in green. (a, b) Detail images show key residues on the protein pocket (gray sticks) and interactions with ligands.