OEApplications 2024.2

Release Highlights 2024.2.0

OMEGA: Thompson Sampling for Torsion Driving

A Bayesian approach to explore conformer space with torsion driving has been added as an alternative to the exhaustive searching of the space in OMEGA. This uses the framework of Thompson sampling to quickly direct the conformer search towards the low energy structures, reducing the time required to find the lowest energy conformer. As such, Thompson sampling is particularly suitable for generating small to moderately sized ensembles, such as used in the FastROCS or ROCS mode. Thompson sampling provides significant speedup for such ensemble generation, particularly for molecules with a large number of rotors.

Conformer ensembles for FastROCS usage are generated with OMEGA using both the standard exhaustive sampling and the newly implemented Thompson sampling, for ~5500 Iridium HT protein bound small molecule crystal structures. Performance between the two sampling methods is compared in terms of RMSD between the generated ensemble and the crystal pose, and in the time required to generate the ensembles. The results of the comparison, as shown in Figure 1 below, show that the accuracy of the generated ensembles, measured in RMSD, remains unaffected when using exhaustive versus Thompson sampling, whereas there is significant reduction in time usage to generate those ensembles when using Thompson sampling, especially as the size of the molecules grows.

../../_images/omega_thompson_mmds.png

Figure 1. Comparison of OMEGA performance between exhaustive and Thompson sampling.

Ligand-based virtual screening performance, using both the exhaustive and Thompson sampling generated ensembles, was also compared and displayed in Figure 2. The comparisons were performed using directory of useful decoys (DUD-Z) datasets containing 38 targets. The results ensure that there is no meaningful change in accuracy when using Thompson sampling for ensemble generation for usage in ligand-based virtual screening.

../../_images/omega_thompson_vs.png

Figure 2. Comparison of performance of ligand-based virtual screening success rate with conformer ensembles generated using exhaustive versus Thompson sampling.

BROOD: Bioisosteric Fragment Replacement in Macrocyclic Peptides

A new pose generation algorithm has been introduced in Bioisostere TK, as well as in BROOD, based on flexible overlay of shape, color, and force fields, as used in pose generation with ShapeFit. The new algorithm generates high quality poses of molecules that are obtained from fragment replacement in Bioisostere TK and BROOD. The robust pose generation algorithm enables usage of Bioisostere TK and BROOD for molecules with complex geometry, including macrocyclic peptides. Figure 3 shows an example of a residue fragment replacement in a macrocyclic peptide.

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Figure 3. Bioisosteric replacement of a residue fragment in a macrocyclic peptide using BROOD.

Eon TK: New Toolkit for Overlay Optimization with Shape and Charge Density

The 2024.2 release introduces Eon TK, a new toolkit for molecular similarity based on shape and electrostatics. This provides toolkit-level access to the existing EON application functionality. Following EON, the new toolkit has both molecular charge density and electrostatic potential as options to use as descriptors of electrostatic properties. Figure 4 shows an example of EON overlay with charge density visualization.

../../_images/eon_electrostatic_overlay.png

Figure 4. EON shape charge density overlay between two molecules.

Eon TK provides tools for molecular overlay optimization with shape and charge density, similarity estimation based on shape and charge density or electrostatic potential, and corresponding hit list building.

Supported Platforms

OS

Versions

Linux

RHEL8/9, Ubuntu20/22

Windows

Win10, Win11

macOS

12, 13, 14

Detailed Release Notes 2024.2

AFITT 3.0.1

Minor internal improvements have been made.

BROOD 4.1.0

Minor internal improvements have been made.

Bioisostere TK 4.1.0

New features

  • A new algorithm, based on OEFlexiOverlay, has been adapted in Build for optimization of generated poses for molecules obtained from fragment replacement. The new algorithm is more robust for optimization of poses for all geometries, including cyclic peptides.

Major bug fixes

  • Query building algorithms in OECreateBroodQuery have been improved for robustness. The improved API automatically includes any associated hydrogen atoms as part of the query fragment. Behavior has also been improved to provide better error behavior against invalid selections.

  • The new methods SetSingleSourceMol and GetSingleSourceMol have been added to OEFragmentOptions to provide flexibility regarding source molecule storage during database building.

Minor bug fixes

  • Some memory management issues have been fixed in Build and Generate.

EON 3.1.0

New Features

  • Supported input and output file formats for EON have been revised to improve clarity.

  • The output csv file now contains additional columns with a rank of hits and best conformer index.

  • The Boolean flag -scoreonly has been added to the EON application to allow passing prealigned molecules that only need to be scored.

Bug Fixes

  • An issue affecting the EON hit list has been fixed. EON now properly uses the best conformer for each database molecule based on shape and charge density scores, instead of the first conformer of the molecule, to generate the hit list.

  • A bug in combining shape and electrostatics gradients has been fixed.

Eon TK 3.1.0

This is the first commercial release of Eon TK.

New features

The following classes are available as preliminary API with the first release of this toolkit.

The following functions are available as preliminary API with the first release of this toolkit.

Zap TK 2.5.0

Minor internal improvements have been made.

OEDocking 4.3.2

Minor internal improvements have been made.

OEDocking TK 4.3.2

New features

Major bug fixes

  • The method Optimize in OEPoseOptimizer is now more robust in optimizing a docked pose. Accordingly, Docking with relaxation in OEPosit is also now more robust.

  • The function OEHasClash now properly recognizes all clashes between a ligand and a protein that were previously mistaken because of some misidentification of covalent bonds.

Minor bug fixes

  • Selection of the best receptor has been improved in OEPosit, ensuring that the correct receptor will always be picked in case of a self-docking.

  • The internal algorithm has been optimized to improve time requirements for OEPosit when working with many receptors and a few ligands.

OMEGA 6.0.0

New Features

  • Supported input and output file formats for OMEGA have been revised to improve clarity.

Minor Bug Fixes

  • OMEGA now properly propagates SD data of molecules when running jobs using MPI.

  • OMEGA no longer reports time used per molecule in the log output, but they are properly reported in the CSV report.

Omega TK 6.0.0

New features

Minor bug fixes

  • User-defined values passed through SetEnergyWindow, SetMaxConfs, and SetRMSThreshold are now properly accounted for, even when the corresponding defaults are range-based.

  • Molecule titles are retained when Build fails in OEOmega with fails to build structure from CT.

  • A verbose log is provided for fragments that fail when Build fails in OEOmega with fails to build structure from CT.

  • The OEOmegaIsGPUReady function has been safeguarded from a rare crash. The function has also been updated to check not only for device 0, but for devices from 0 to 100.

MolProp TK 2.6.5

Minor internal improvements have been made.

PICTO 5.1.2

New features

  • A feature has been added that allows a user, in the view preferences, to increase the limit on the maximum number of atoms in a molecule when reading or writing in molecule-specific file formats.

OEDepict TK 2.5.5

Minor internal improvements have been made.

pKa-Prospector 1.2.4

Minor internal improvements have been made.

QUACPAC 2.2.5

Minor internal improvements have been made.

Quacpac TK 2.2.5

Minor bug fixes

ROCS 3.7.0

New Features

  • The utility application CheckCff has been restructured to provide the same underlying functionality for color assignment as that of the Prep method from the OEOverlapPrep class. The following new command line parameters have been added.

    • -removeDups: Flag if color atoms within a certain distance from each other should be removed.

    • -minDistance: Minimum distance between color atoms for them to be treated as duplicates.

  • The modified CheckCff always generates a report file in .csv format and -report can be used to provide a nondefault name to the report file.

Minor Bug Fixes

  • --help -chemff for the CheckCff now properly displays all of the available options.

Shape TK 3.7.0

New features

Minor bug fixes

SiteHopper 2.1.1

Minor internal improvements have been made.

SiteHopper TK 2.1.1

Minor bug fixes

SPRUCE 1.6.1

Minor internal improvements have been made.

New features

  • Command line arguments have been added to control the gap and extend penalties for the sequence alignment used for loop building.

Spruce TK 1.6.1

New features

  • OEBuildSidechains now minimizes target side chains by default. Minimization can be controlled by setting minimizeSidechains and minimizeSidechainsShell options in the OESidechainBuilderOptions class.

  • A feature has been added to support a next generation mmCIF feature, such that when an mmCIF file provides a connectivity record for the heterogens, Spruce will no longer look up the heterogen in the Chemical Component Dictionary but trust the input provided.

  • A feature has been added that allows in-plane flipping of a single hydrogen on a double bonded nitrogen, when a clash is detected as part of hydrogen bond network optimization.

Major bug fixes

  • An issue has been fixed related to using the OEHeterogenMetadata class, where the provided SMILES string was not respected for tautomer generation; when tautomers were not provided; and when the title (residue name) collided with existing residue names in the stored Chemical Component Dictionary.

  • An issue has been fixed related to covalently bound ligands, where the pre-reaction input SMILES and related tautomers were not adjusted properly when accounting for the formed covalent bond.

  • An issue has been fixed where the Spruce filter deleted single (disconnected) amino acid residues when they were marked HETATMs and were not real “floating” residues in part of the regular protein sequence.

Minor bug fixes

  • OEMutateResidues, OEMutateResidue, and OEBuildSidechains now reduce failures arising from clashes by using shell minimization by default.

  • An issue has been fixed that caused HEME-like molecules to be excluded from the stored chemical component database.

Documentation changes

  • Information has been added about setting and getting minimizeSidechains and minimizeSidechainsShell options in the OESidechainBuilderOptions class.

SZMAP 1.7.1

Minor internal improvements have been made.

Szmap TK 1.7.1

Minor internal improvements have been made.

SZYBKI 2.8.0

Minor internal improvements have been made.

Szybki TK 2.8.0

New features

  • The constant SAGE_OPENFF refers to the latest version of the Sage OpenFF force field.

VIDA 5.0.7

Minor internal improvements have been made.