OEApplications 2022.2¶
Release Highlights 2022.2.2¶
The OEApplications 2022.2.2 is a bug-fix of the OEApplications 2022.2.1 release, and depends on OEToolkits 2022.2.2.
Release Highlights 2022.2.1¶
MCS based fix during OMEGA Conformer Generation¶
The ability to constrain a fragment of the molecules during conformer generation with torsion
driving in OMEGA and the OMEGA toolkit
has been extended to include fixing based on maximum common
subgraph (MCS) match. In this mode of fixing, the MCS between the template fixmol and the generated
molecule is determined, and subsequently that common subgraph portion of the generated molecule is
fixed to the proved conformer of the fixmol.
The MCS based fixing during conformer generation can be turned on by setting
SetFixMCS to true for use in the
OMEGA toolkit. Additional
API points have also been added to allow control during MCS search. A new flag -fixMCS is
available in the OMEGA application to facilitate this.
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OMEGA generated conformers for two different molecules, with MCS based fix against a single bound ligand pose. Figure shows that with MCS based fix, two different fragments are fixed during conformer generation of the two different molecules.
New ShapeFit Algorithm for Pose Prediction¶
The algorithm for pose prediction with the SHAPEFIT
method has been modified. The new algorithm simultaneously optimizes the shape and
chemical similarity between the fit molecule and bound ligand, and intra-molecular
force-field energies of the fit molecule. The new simultaneous optimization algorithm
replaces the previous adiabatic optimization algorithm and is more robust. The new
algorithm also offers flexibility to use different forcefields and uses the
SAGE force field by default. Another advantage of the new
algorithm is that it is capable of producing multiple distinct poses when desired.
The new algorithm is automatically reflected in both the OEPosit toolkit
and the POSIT application. ShapeFit is also now available in the
OEDocking TK as an independent API OEShapeFit.
Cross docking experiments based on the 22 diverse kinase types presented in
[Tuccinardi-2010] shows that ShapeFit accuracy is unaffected between the
previous and the new algorithm (when accuracy is measured as RMSD <=2.0).
A balanced cross-docking set of 20,000 points, where points are equally distributed
over the various similarity regions and kinase types, was used. However, we see
clear indication that generating multiple poses helps increase the pose prediction accuracy.
A separate self-docking study based on the highly trustworthy iridium dataset ([Warren-2012])
with 280 ligand-protein structures shows that new algorithm predicts poses that are
closer to the x-ray crystallographic poses.
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Left: Comparison of ShapeFit accuracy in a cross-docking experiment between the existing and the new algorithm. The x-axis shows the tanimotocombo similarity between the ligand and the bound ligand present in protein complex. The Y-axis shows the fraction of accurately predicted poses based on being within 2 angstroms of the experimental pose. Right: Comparison of ShapeFit accuracy in a self-docking experiment, between the existing and the new algorithm. Axes show the RMSD of generated poses with respect to the experimental pose.
Protein-ligand Optimization with ff14SB forcefield and PB solvent model¶
Protein-ligand Optimization with ff14SB-OpenFF force field and Poisson-Boltzmann (PB) solvent model
is now available both in SZYBKI and the SZYBKI toolkit.
In the SZYBKI TK, the functionality is available through the OEFixedProteinLigandOptimizer
and the OEFlexProteinLigandOptimizer APIs, and can be enabled by setting
PB as the value in SetSolventModel.
In SZYBKI both the OptLigandInDU and OptimizeDU applications now accept pb as value
for -solventModel.
Optimization of 244 highly trustworthy x-ray structures of protein-ligand complexes from the
iridium dataset ([Warren-2012]) with and without PB solvation
and with ff14SB-Sage forcefield shows better accuracy for the optimized ligand poses when PB solvation
is turmed on. Accuracy is measured as the RMSD between the crystallographic ligand pose and the optimized
pose. On an average PB solvation optimized structurs have an RMSD of 0.31 angstroms, compared to a value of
0.55 angstroms when explicit solvation is not turned on. A paired T-test suggests that the avergae improvement
of 0.24 angstroms is statistically significant with a p value of 0.00001. Turing on the solvation effects also
removes any significant deviations (RMSD > 2 angstroms) of pose, as was seen for a few cases when optimization was
performed in vacuum.
Comparison of RMSD for Flexible protein-ligand optimization of x-ray structures with and without PB solvation and with ff14SB-Sage forcefield.¶
New BROOD Fragment Databases¶
Two new BROOD fragment databases, brood-database-ChEMBL31 and brood-database-ChEMBL31_lite,
built from the latest version of ChEMBL, have been generated and are made available. The
brood-database-ChEMBL31 contains all possible fragments up to 3 attachment points, whereas
the brood-database-ChEMBL31_lite is curated to prioritize fragments with medicinal relevance.
Limited validation, with 29 different queries accross 14 molecules, shows that the number of hits of
druglike molecules obtained from the new databases are within 1% of those generated from the existing
database brood-database-chembl-3.0.0. Comparison of belief score, a measure of potential activity
of the generated hits, also shows that the hits generated from the new databases are at least as
good as those generated from the existing database.
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Left: Comparison of the number of hits of druglike molecules using the brood-database-chembl-3.0.0 (ChEMBL20), brood-database-ChEMBL31 (ChEMBL31) and brood-database-ChEMBL31_lite (ChEMBL31_lite) fragment databases. Right: Comparison of the belief score distribution of all the hits generated using the ChEMBL20, ChEMBL31 and ChEMBL31_lite fragment databases.
Supported Platforms¶
OS
Versions
Linux
RHEL7/8, Ubuntu20/22
Windows
Win10, Win11
macOS
11, 12
General Notices¶
Support for Ubuntu22 has been added. Support for Ubuntu18 has been dropped.
This is the last release to support macOS 11. Support for macOS 13 will be added in the next release.
This is the last release to support RHEL7. Support for RHEL9 will be added in the next release.
Detailed Release Notes 2022.2¶
BROOD 3.2.0¶
Fall 2022
New Features¶
Two new fragment databases, ChEMBL31_lite and ChEMBL31, are now available. Refer to the BROOD Fragment Database section for details about these new fragment databases.
Major bug fixes¶
An issue that caused BROOD to generate incorrect
Molecular Tanimoto Combowith correspondingp (active)has been fixed.An issue that caused CHOMP to generate a much larger database than expected, by generating too many conformers per fragment, has been fixed.
Zap TK 2.4.4¶
Minor internal improvements have been made.
OEDOCKING 4.2.0¶
Fall 2022
New features¶
The Posit application now uses the new OEShapeFit API for flexible fitting with Shape/Color and Forcefield. The new algorithm replaces the currently existing ShapeFit algorithm that uses adiabatic optimization. A modified ShapeFit algorithm optimizes the shape and chemical similarity between the fit molecule and bound ligand present in the reference design unit, along with intra-molecular forcefield energies of the fit molecule. The SAGE ligand force field is used during this optimization.
Spruce Filter was added to MakeReceptor, to assist in structure standardization prior to structure preparation.
Minor bug fixes¶
Posit now prints out more concise warning messages.
OEDocking TK 4.2.0¶
New features¶
Two new preliminary API classes, OEShapeFit and OEShapeFitResults have been added which provides functionality for pose generation based on flexible fitting with Shape/Color and Forcefield.
The adiabatic optimization algorithm of
ShapeFitmethod for pose generation in OEPosit has been replaced by a new simultaneous flexible fitting algorithm, as implemented in OEShapeFit. The new algorithm uses Sage as the default forcefield, instead of MMFF.Two new methods, SetFlexiOverlayOptions and GetFlexiOverlayOptions, have been added to OEPositOptions to expose parameters related to OEShapeFit in OEPosit.
Major bug fixes¶
An issue that caused a segmentation fault when using CacheScoringSetup has been fixed.
Documentation changes¶
New C++ and Python examples have been added to the Flexible Overlay Optimization with OEShapeFit API section that demonstrate how to flexibly fit input multi-conformer molecules into a design unit that contains a bound ligand.
OMEGA 4.2.1¶
Fall 2022
Omega TK 4.2.1¶
New features¶
The ability to fix a part of a molecule during conformer generation based on maximum common substructure (MCS) has been added. The following new methods have been added to the OEConfFixOptions to enable this functionality:
New methods SetIgnoreStereo and GetIgnoreStereo have been added to OEMolBuilderOptions to allow continuation of conformer generation when specified stereo signatures in a molecule could not be honored.
New methods SetMaxEnumConfs and GetMaxEnumConfs have been added to OEMolBuilderOptions to allow specifying the maximum number of conformers to be generated from ring enumeration, nitrogen enumeration and/or hydrogen sampling.
Verbose mode logging now reports torsion angles sampled, along with the rules, during torsion driving.
Minor bug fixes¶
Conformer generation with OEOmega.Build or OEMolBuilder.Build now fails correctly when specified stereo signatures on a molecule cannot be honored. The existing behavior, to carry on even if stereo signatures could not be honored, can be obtained be setting IgnoreStereo to
true.Ring fragment building during OEOmega.Build, OEFragBuilder.Build, OEMolBuilder.Build, or GenerateMissingFrags now properly honors the SetFragKeep parameter regarding the maximum number of generated fragment conformers to be kept.
MolProp TK 2.6.1¶
New features¶
A new free function, OECheckXLogXType, that returns
trueif an atom has a valid XLogPType has been added.A new free function, OECheckXLogXTypes, that returns
trueif all atoms excluding hydrogen in a molecule have valid XLogP types has been added.
Minor bug fixes¶
An issue with filter output failure reporting, where failure due to the rules ALLOWED_ELEMENTS and ELIMINATE_METALS was not included in the output table, has been fixed.
PICTO 4.6.0¶
Fall 2022
New features¶
The ability to display explicit hydrogens in the sketcher from input SMILES, and when opening files with explicit hydrogens, has been added.
Aromatic views for Kekule, Circle, and Dashed has been added.
A “Fit in Window” feature has been added.
The ability to toggle display hydrogens has been added.
A toggle to display super atoms has been added.
The ability to display atom labels based on stereo, locants, indices, and atom annotation maps has been added.
When an atom is clicked in the sketcher, the input cursor will move to that atom in the SMILES to allow easier modification of the SMILES input at a specific location of the molecule.
Deleting mulitple molecules when selecting with the eraser is now available.
The ability to highlight multiple molecules when selecting through SMILES input has been added.
Major bug fixes¶
PICTO now properly highlights selected SMILES input in sketcher.
SMARTS queries and Send to SMARTS now works with separate molecules (separated by a pipe in the SMILES input).
Files with explicit hydrogens will now display the explicit hydrogens and allows a query to match with the explicit hydrogens.
Minor bug fixes¶
An issue where Compound Name displays were not properly formatted has been fixed.
An issue where atoms with an atomic number of 119 and above were not displayed with their atomic number has been fixed.
Highlighted atoms from SMARTS query matches now resets after the SMARTS query is deleted.
When the selection in sketcher is unselected, the corresponding input selection in the SMILES will now be unselected.
The checkbox for retaining explicit hydrogens now resets when the molecule displayed as SMILES has explicit hydrogens converted to implicit, which happens when selections are made in the SMILES .
OEDepict TK 2.5.1¶
Minor internal improvements have been made.
QUACPAC 2.2.1¶
Minor internal improvements have been made.
Quacpac TK 2.2.1¶
Minor internal improvements have been made.
Shape TK 3.5.1¶
New features¶
The following new methods have been added to OEOverlayOptions to improve flexibility in defining parameters:
A new overload for the method CreateGrid has been added that takes a transform object as an additional argument that is applied after the grid is generated.
Major bug fixes¶
Default forcefields in OEFlexiOverlapOptions now ignores electrostatic interactions, as electrostatics appear to have negligible effects on optimized overlaid structures. Ignoring the electrostatic interactions also improves efficiency of optimization for the corresponding OEFlexiOverlapFunc.
The default for OEOverlapFunc in OEFlexiOverlayOptions now consists of
Shapeonly and noColor. The defaultShape scoreused is Overlap.
Minor bug fixes¶
A mismatch between the Hermite grid and the input molecule has been fixed.
The maximum value on Hermite resolution parameter has been increased from 30 to 100.
Documentation changes¶
The following C++ and Python examples have been added to demonstrate how to use new preliminary APIs:
Two new C++ and Python examples have been added to the Flexible Overlay with Shape and Forcefield section that show flexible overlay optimization of the fit molecules against a single reference molecule conformer.
When using BestOverlay only one conformer that has the highest tanimoto-combo similarity to the reference molecule is returned.
Sitehopper TK 2.0.2¶
Minor internal improvements have been made.
SPRUCE 1.5.1¶
Fall 2022
New features¶
When providing a site-residue to Spruce, the output title and output filenames of apo design units will now use that site residue in the name. Previously, the residue closest to the center of the binding site was used.
Spruce TK 1.5.1¶
New features¶
If a site-residue is provided to OEMakeDesignUnits, the output design unit title now has the site residue in the title for apo structures. Previously, the residue in the title was the residue closest to the center of the binding site.
Standardization using Spruce Filter now checks for metal chelation before forming disulfide bridges.
Major bug fixes¶
An issue causing accumulation of generic data on the molecule components stored in the design unit object during prep has been fixed. This accumulation led to large memory consumption, slow preparation, and larger file size.
Szmap TK 1.6.5¶
Minor internal improvements have been made.
SZYBKI 2.5.1¶
Fall 2022
New features¶
Output for
freeform -calcconfnow adds dG, local strain, and global strain values to tracked conformer output files as SD data.
Minor bug fixes¶
A misleading error message produced by SZYBKI when run with
freeform -ffieff_mmff94orfreeform -ffieff_mmff94s, without specifying the receptor with eitherszybki -proteinorszybki -complex, has been improved.Values of dG, local strain, and global strain have been added to the
tracked_rstfile when freeform is run with thefreeform -trackoption.Case-insensitive values for
freeform -ffare now accepted in SZYBKI.
Szybki TK 2.5.1.2¶
Possible crash in OEFixedProteinLigandOptimizer_Optimize and OEFlexProteinLigandOptimizer_Optimize methods have been fixed.
Szybki TK 2.5.1.1¶
New features¶
Optimization of bound ligands with ff14SB/Sage and ff14SB/Parsley force fields with PB solvation forces in rigid and partially flexible receptors is now available.
Setting the force field to PARSLEY_OPENFF131 or SAGE_OPENFF200 now references the most recent official versions of those two parameterizations which are OpenFF_1.3.1 and OpenFF_2.0.0 respectively. Older versions are still available from the OEForceFieldType namespace.
Final ligand geometry is now checked when large initial clashes occur while using OEFixedProteinLigandOptimizer and OESz_OEFlexProteinLigandOptimizer for optimization of a ligand inside a protein receptor. In most cases, clashes are successfully relaxed; however, in some cases they can lead to a non-physical minimum which is characterized with distorted geometry. Such results can now be detected by checking the return values of methods OEFixedProteinLigandOptimizer_Optimize and OEFlexProteinLigandOptimizer_Optimize.
Major bug fixes¶
An issue with torsion scan for alkanes using MMFF has been fixed.
OEFixedProteinLigandOptimizer_Optimize and OEFlexProteinLigandOptimizer_Optimize now fails properly when optimization leads to a non-physical state of a molecule, characterized with distorted geometry. Such non-physical optimization can sometimes happen when the starting configuration of a protein-ligand complex contains high overlaps.
Minor bug fixes¶
A warning regarding ‘invalidation of receptor’ upon optimization using the OEFlexProteinLigandOptimizer class has been removed.