A method for sampling macrocyclic conformational space (see macrocycle mode below) has been added to OMEGA. This method uses a distance geometry approach to generate conformer ensembles for macrocyclic molecules. It can also be applied to linear and small ring-containing molecules but is substantially slower than OMEGA classic.
OMEGA now includes five modes:
The classic mode is the original customizable OMEGA interface and the macrocycle mode uses an adaptation of the distance geometry method of Spellmeyer et al. [Spellmeyer-1997]. All other modes use fixed optimal parameters of the original OMEGA interface for various downstream applications:
rocs: -maxconfs = 50 pose: -maxConfRange = "200,800", -rangeIncrement = 8 dense: -strictstereo = false, -ewindow = 15, -maxtime = 3600, -rms = 0.3, -maxrot = 20, -maxconfs = 20000
A new command, oeomega, has been added to invoke these modes. In addition, the original omega2 command has been retained for backward compatibility. In all modes except macrocycle, OMEGA automatically detects macrocycles and sends them to the fail file. The following are examples of oeomega commands to run these modes:
oeomega classic -in drugs.smi -out drugs_classic.oeb.gz oeomega macrocycle -in drugs.smi -out drugs_macrocycle.oeb.gz oeomega rocs -in drugs.smi -out drugs_rocs.oeb.gz oeomega pose -in drugs.smi -out drugs_pose.oeb.gz oeomega dense -in drugs.smi -out drugs_dense.oeb.gz
There are now two built-in torsion libraries in OMEGA in classic mode: the original PDB-derived torsion library and a new CSD-derived library, “Guba,” based on work from Roche using the frequency of particular angles found in the CSD for common torsion types [Guba-2016]. Introduced in the 2017.Oct Toolkits Release, this torsion library contains more than 500 new entries and complements the existing library, which is primarily based on an analysis of structures found in the Protein Data Bank (PDB). A new flag, -torlibtype, has been added to the OMEGA classic mode that allows users to specify which of the two libraries should be used.
Two new options, macrocycle and nonmacrocycle, have been added to the -filter flag of FILTER. macrocycle is used to remove non-macrocycle molecules in the input file; nonmacrocycle is used to remove macrocycle molecules.
Four new options, mmff94smod, mmff94smod_NoEstat, mmff94smod_Trunc, and mmff94smod_Sheff, have been added to both the -buildff and -searchff flags of OMEGA classic. mmff94smod modifies the torsion interaction parameters of mmff94s to produce the desired equatorial conformers for monosubstituted cyclohexanes. mmff94smod_NoEstat includes all mmff94smod terms except Coulomb interactions. mmff94smod_Trunc excludes both Coulomb interactions and the attractive part of Van der Waals interactions. mmff94smod_Sheff includes all mmff94smod terms; the Sheffield solvation model is used during the calculation of energies for the conformers generated. mmff94smod_NoEstat is now the default for both -buildff and -searchff.
A Pan Assay Interference Compounds (PAINS) filter has been added to the -filter flag of FILTER by adapting the supplementary material from the original [Baell-2010] paper. The PAINS filter can be used as a prefilter set for screening or, more interestingly, as a post-processing filter to identify possible protein-reactive or other assay-confounding functionalities within hits. Any hits so identified will require more care to determine if the measured activity is valid.