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.

Conformers for 3VV8_8838 Conformers for 4BFD_4239

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.

../../_images/RMSD_Cross_Docking.png ../../_images/RMSD_Self_Docking_Inset.png

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.

../../_images/pb_opt_rmsd.png

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.

../../_images/filtered_molecules.png ../../_images/Belief_score_lineplot.png

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

AFITT 2.6.2

Fall 2022

Minor internal improvements have been made.

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 Combo with corresponding p (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.

EON 2.4.0

Fall 2022

Minor internal improvements have been made.

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

Major bug fixes

  • An issue that caused a segmentation fault when using CacheScoringSetup has been fixed.

Documentation changes

OMEGA 4.2.1

Fall 2022

New features

  • A new command line parameter, -fixmcs, has been added to provide enhanced support to fix part of a molecule during conformer generation based on maximum common substructures (MCS).

Minor bug fixes

  • OMEGA now generates report files with appropriate content.

  • Log files from OMEGA now contain newly generated titles of molecules for untitled molecules.

Omega TK 4.2.1

New features

Minor bug fixes

MolProp TK 2.6.1

New features

  • A new free function, OECheckXLogXType, that returns true if an atom has a valid XLogPType has been added.

  • A new free function, OECheckXLogXTypes, that returns true if 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.

pKa-Prospector 1.2.0

Fall 2022

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.

ROCS 3.5.1

Fall 2022

Minor internal improvements have been made.

Shape TK 3.5.1

New features

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 Shape only and no Color. The default Shape score used 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 2.0.2

Fall 2022

Minor internal improvements have been made.

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 1.6.5

Fall 2022

Minor internal improvements have been made.

Szmap TK 1.6.5

Minor internal improvements have been made.

SZYBKI 2.5.1

Fall 2022

New features

  • Output for freeform -calc conf now adds dG, local strain, and global strain values to tracked conformer output files as SD data.

Minor bug fixes

Szybki TK 2.5.1.2

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

VIDA 5.0.3

Fall 2022

Minor internal improvements have been made.