Identifying Ligand Exit Vectors

An exit point (or exit vector) defines the specific atom and spatial trajectory from which a bound ligand can be chemically extended without sterically clashing with the receptor pocket.

Accurately defining these vectors in ICM is essential for directing rational compound optimization. Mapping growth trajectories toward unoccupied sub-pockets, adjacent fragments, or bulk solvent forms the foundation for key design workflows:

• Fragment Growing & Linking: Directing R-groups into adjacent binding sites to capture new interactions, or designing linkers between distinct bound fragments.
• PROTAC Design: Finding solvent-exposed atoms for linker attachment without disrupting the target binding pose.
• Library Enumeration: Defining spatial constraints for tools like RIDE or CombiRIDGE, ensuring that enumerated libraries (like the VAST space) only follow structurally viable paths.
• Probe Attachment: Adding bulky tags or fluorophores without compromising the parent ligand's affinity.

The exit point scan in ICM tries to attach groups below to each hydrogen atom "*CCC" // "*OCC" // "*C(=O)NC" // "*NC(=O)C"

To run this:

• Setup the ligand and receptor in the ligedit tab.
• Go to Advanced/Find Exit Attachment Points
• A table of the results will be displayed

For every hydrogen atom in the ligand it returns the following information. The table is interactive if you click on a row it will show you the hydrogen exit point. A low Score and RMSD represents the best attachment point.

• apo - Exit Point Atom (Hydrogen) name
• NN_Score - the average RTCNN binding score for all these attachments for this hydrogen
• CoreRmsd - average core deviation of the ligand when an attachment is made - try to keep low