FEP Pose Generation with MCS Docking Ligand Alignment
FEP Pose Generation with MCS Docking Ligand Alignment 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.
The MCS docking workflow can be run through the MCS Docking Ligand Alignment Panel in Maestro (Task > Browse > Structure Alignment > MCS Docking Ligand Alignment), from the command line ($SCHRODINGER/run mcs_alignment_workflow.py) or as a protocol in LiveDesign called “MCS docking workflow”.
Workflow Overview
This workflow performs Glide docking with core constraints constraining the maximum common substructure (MCS). In the mode “Allow docked ligands to become reference ligands” (standard mode on command line invocation) every successfully docked ligand can be added to the pool of references to become core constraints. For each new ligand being docked, the reference with the largest Tanimoto similarity is used as reference for core constraints. The workflow will fall back to flexible ligand alignment for ligands which are deemed sufficiently similar to the associated reference to improve speed as well as for ligands where docking fails to produce a pose. This default behavior can be changed using the “Docking-based alignments only” option from the panel and the command line input using docking_alignment_only True.
In LiveDesign the workflow can be run on a batch of compounds (determined by the LiveDesign protocol batch size, 10 by default), and in the mode “Allow docked ligands to become reference ligands” new references may be selected from within the batch. It is also possible to run this protocol with multiple receptor structures.
See the publication for more information.
Domain of applicability
MCS docking ligand alignment is designed for alignment of a relatively small number of ligands (a few hundred maximum) to a reference set. In case of a large number of ligands to align using Glide with core constraints is recommended. Due to the iterative addition of references the workflow does not allow for parallelization/utilization of multiple cores.
If the topology of the MCS in the series differs, the part of the ligand constrained for docking will be too small. There are 2 additional modes (mode Shape / mode FEP) that are only from the command line. Mode Shape will enable a simple Shape bias with the reference ligand, producing looser fit poses with more tolerance. mode FEP is designed for producing better alignments suitable for FEP calculation.
Sample input
mode STATIC
default_grid replaced
lig_file replaced
reflig_file replaced
Minimum_similarity 0.3
Docking_aligment_only False