FEP Pose Generation with Glide

FEP Pose Generation with Glide Contents

 

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.

Glide can be run from the Ligand Docking Panel DEPRECATED in Maestro, from the command line, or as a model in LiveDesign. The models in LiveDesign usually combine Glide docking with custom LigPrep and LigFilter stages.

Workflow Overview

Comparing usage of different Glide constraints

Constraint Pros Cons
No constraints (Use Glide Docking Protocol in LiveDesign) Easy to set up Sometimes the overlap to reference is not perfect
H-bond constraints (Use Glide Docking Protocol in LiveDesign) Usually possible to achieve key contacts to be present No control over rest of the ligand, and key contact may be satisfied even if the core or shape doesn’t match
Core constraints (Use Glide Docking Protocol with Reference Ligand in LiveDesign) Overlap to reference is better (compared to using no constraints) Many constraints don’t work well together, more difficult to set up right
Shape constraints (Use Glide Docking Protocol with Reference Ligand in LiveDesign) Overlap to reference is usually better (compared to using no constraints). Helpful for common part which cannot be matched with MCS well May be difficult to align idea and reference well enough for FEP to detect the non-changing parts of the ligand

 

Note:

While it is common to include multiple constraints in a docking protocol, too many constraints (e.g. large SMARTS in an MCS and H-bond constraints) can lead to failures due to how the core snap and pose filtering algorithms work. One may need to manually adjust the SMARTS to include fewer atoms in order to avoid this issue (see The glide Command)

Glide (no constraints)

  • Example .in file:

    • GRIDFILE replaced

    • LIGANDFILE replaced

    • PRECISION SP

  • Simple Glide docking can be used in cases where the binding site easily accommodates ligand substitutions without the scaffold moving too much

  • It is possible to add H-bond etc. constraints to Glide docking via the Ligand Docking panel in Maestro. In all but the simplest case above it is recommended for LiveDesign models to first set up a working docking model in Maestro, and then upload the .in and grid .zip files to the LiveDesign model page

  • Sometimes if you are not obtaining the desired poses you may need to adjust other keywords like VdW scaling, expanded sampling, macrocycle sampling, number of poses to keep in intermediate stages, etc.

  • Rings are by default not sampled but we look them up from a ring template database (https://support.schrodinger.com/s/article/958), if your compound contains a ring that is not contained, you can either generate the ring templates yourself using $SCHRODINGER/utilities/ring_templating (and use this fils also as input in a LiveDesign model), or use the advanced conformation generation (ConfGenX) for on-the-fly ring conformation generation with the following keywords:

    • _CONFGENX_MODE rdkit

    • _CONFGENX_OPTIMIZER True

    • _NUMCONF_CONFGENX 1000

    • _USE_CONFGENX True

  • Generate all plausible protomer and tautomer states as well as non-interconvertible poses (e.g. ring flips if rotation is hindered) and run group corrections in FEP (currently not possible in LiveDesign)

  • For LiveDesign it is recommended to generate only one state and pose, otherwise the FEP runner will choose a random pose from the set of poses

  • Always check your poses visually before running FEP, otherwise you may risk wasting valuable GPU resources on a suboptimal pose

Glide (core constraints)

  • Example .in file:

    • GRIDFILE replaced

    • LIGANDFILE replaced

    • PRECISION SP

    • REF_LIGAND_FILE replaced

    • USE_REF_LIGAND TRUE

    • CORE_DEFINITION mcssmarts

    • CORE_RESTRAIN TRUE

    • CORECONS_FALLBACK TRUE

  • Core constraints can be used to fix the ligand positioning to a reference 3D structure. This is useful to have a tighter overlap between the compounds for FEP.

  • For LiveDesign it is again advised to set up a working docking model first in Maestro and this type of docking has to be performed with the Glide Docking Protocol with Reference Ligand. This protocol requires the presence of either the CORE_RESTRAIN or SHAPE_RESTRAIN keyword

  • Docking with core constraints happens in two stages, first Glide tries to snap the ligand to the MCS SMARTS or the manually specified SMARTS, but if this fails and if the CORECONS_FALLBACK keyword is set to True, it then tries to generate conformers and runs a filter based approach to find similar conformations to the reference pose

  • Often it is useful and easy to set up to have a reference molecule which only contains the core substructure and the CORE_DEFINITION allheavy keyword in the .in file. This makes definition of the substructure easier than editing a SMARTS and avoids multiple matches of the SMARTS

  • The CORE_POS_MAX_RMSD keyword can define how tight the overlap should be

  • The CORE_FILTER keyword can also be used to filter out non-matching states from LigPrep instead of using LigFilter

Glide (shape constraints)

  • Example .in file:

    • GRIDFILE replaced

    • LIGANDFILE replaced

    • PRECISION SP

    • SHAPE_REF_LIGAND_FILE replaced

    • SHAPE_RESTRAIN TRUE

  • Shape constraints can be used to fix the ligand positioning to a reference 3D structure if the same is difficult by defining SMARTS (e.g. in case of nontrivial scaffold hopping). This is useful to have a tighter overlap between the compounds for FEP, however, sometimes it’s quite difficult to have a good overlap between scaffold hopping compounds in FEP (check the detected common scaffold in the FEP panel)

  • For LiveDesign it is again advised to set up a working docking model first in Maestro and this type of docking has to be performed with the Glide Docking Protocol with Reference Ligand. This protocol requires the presence of either the CORE_RESTRAIN or SHAPE_RESTRAIN keyword

Ensemble docking

  • Occasionally we want to dock compounds into multiple receptor structures since different chemical series might be accommodated by different protein conformations

  • This is possible in Maestro e.g. in the XGlide panel, the Virtual Screening Workflow panel.

  • In LiveDesign we have two protocols to perform this type of calculation:

    • Glide Docking with Auto Grid Selection: This model first calculates the similarity (MCS similarity or Tanimoto similarity) to all reference ligands associated with the provided grid files and docks the compound into the receptor grid associated with the ligand with the highest similarity to the idea ligand

    • Multigrid Docking Workflow: This model docks the idea compound into all provided receptor grids and returns the pose with the lowest docking score from all grids

 

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