Ligand Alignment for FEP Pose Generation
Where to run it
Note:
The new FEP+ Pose Builder Panel is Schrödinger’s preferred tool for pose generation for FEP. It has outperformed other methods on benchmarks, and incorporates many of the best practices shown in this page that would otherwise have to be done manually.
Ligand Alignment, which is not a rigid superposition but instead includes conformational sampling, can be run through a panel called the Ligand Alignment Panel in Maestro, or from the command line $SCHRODINGER/utilities/align_ligands or $SCHRODINGER/run -FROM psp tug_align.py for macrocycles.
Workflow Overview
Flexibly aligns small molecule and macrocycle structures in 3D. It includes a series of methods to address various use cases, such as the alignment of ligands from a congeneric set or from a structurally diverse set.
Fast to use when working with a congeneric series of ligands where R-group modifications are not expected to clash with the receptor or make any new interactions (typical example when the R-group is pointing towards solvent or opening a new sub-pocket). Some people use this approach, rather than docking, prior to FEP, to favor an optimal overlay of most parts of the molecules (and hence ensure a good camping by the FEP mapper), and then relieve potential clashes with manual refinement. This method is also useful if ligands cannot be docked due to clashes with the receptor, but when a starting pose for FEP is needed in order to prove non-binding. However, be careful with submitting a pose with unresolvable clashes (e.g. ring spears, overlapping groups, or backbone clashes) for FEP.
Guidance
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Make sure to check the “Ligands contain macrocycles” if your ligand has some macrocyclic character.
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Switch from Automatic to User-specified reference picking.
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If the ligand alignment results in suboptimal or unexpected overlay, one can try to:
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Pick another reference ligand to align to
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Use other common substructure constraints: MCS, SMARTS, or Largest common Bemis-Murcko scaffold (default)
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Tip:
In the Ligand Alignment panel, checking the option “Overwrite existing entries” (at the bottom) is a convenient way to prevent the multiplication of groups of aligned ligands and keeps the entry list tidy.