This is a major new release of BROOD, OpenEye’s fragment replacement search program. This release fixes all known bugs from v1.0. It includes significant re-working of the scoring methods. Most notable among these are that the attachment geometry score is now used as a cutoff to assure that all poses have reasonable attachment geometries, but fragments are ranked according to their shape plus chemical similarity or their shape plus electrostatic similarity. Further, several steps have been taken to eliminate the bias towards “over-colored” fragments (including implementing Tanimoto color rather than scaled color). Last, but not least, there are dramatic improvements to the databases and database content, as well as CHOMP, the program for user-generated databases. The two databases provided with BROOD now contain the most common fragments found in vendor compounds, are more complete, are better filtered, have improved conformer sampling and contain proper MMFF partial charges. We believe this release is a major step toward maturation of the fragment searching methods available from OpenEye.
BROOD and CHOMP Features:
Improved conformers of constructed analog molecules to be as close to the original build molecule conformers as possible.
Added each score component to the report file as well as to the SDTags.
Added the frequency information to the SDTags.
Added bondOrder flag that by default requires attachment point bond order to be the same as those in the query fragment.
Changed color scoring from scaled-color to Tanimoto-color in order to prevent over-scoring of highly colored fragments.
Added shapeCut parameter to prevent very bad overlaps from appearing in hitlist when no good matches are found in the database.
Added attachCut parameter to eliminate fragments with poor attachment geometries regardless of how good their shape and chemical similarity is.
Removed the attachment score as a component to the color combo and ET combo score. Color combo is now the sum of the shape and chemical color Tanimoto scores. ET combo is now the sum of the sum of the shape and the electrostatic Tanimoto scores.
Improved and clarified the handling of 2D and 3D coordinates in the query fragment and the build molecule. This includes generating depiction coordinates for the built analog molecules when the input build molecule doesn’t contain 3D coordinates.
Improved documentation of hitlists and database generation.
Updated OEChem to include the ability to read SDTags from the .oeb formatted database file.
Added info file to CHOMP runs.
Added warnings when short hitlists are encountered.
Added fragment filtering progression and hitlist size to info file.
Cleaned up the column ordering in the report file.
Properly handle cases with more than three attachment points.
Changed :option: -sdtag default from “true” to “verbose”.
Improved reporting of early initialization problems.
BROOD and CHOMP Bug Fixes:
Built analog molecules are now aligned with the input build molecule.
Fixed bug that caused the query fragment to be moved before the search began and never replaced.
Fixed bug that prevented the proper behavior of the :option: -build flag in conjunction with the :option: -ET flag.
Corrected bug related to the :option: -fileCharge flag.
Fixed query fragment to build molecule matching bug related to differing aromaticity models.
Fixed two CHOMP bugs that prevented the :option: -smarts flag from working properly.
Removed potential for double-counting non-default attachment scale parameter when used with the :option: -ET flag.
Fixed memory leak in large hitlist management system.
Improved database fragment content to include common fragments of all sizes up to 15 heavy atoms (or 350 MW).
Generate, use and attach fragment frequency information to each fragment.
Developed new methods for filtering fragments rather than filtering whole molecules before fragmentation.
Eliminated primary-fragment database.
Added simple chemical complexity filters.
Improved perception of anionic hydrogen-bond perception.
Database Bug Fixes:
Fixed partial charge errors that occurred on some attachment point methyl groups.
Fixed polar-proton partial charge error.
Removed duplicate fragments.
Fixed ring-opening bug that fragmented most aliphatic heterocycles, thus preventing them from occurring in the original database.
Fixed branching bug that prevented some unusual branching patterns from occurring in the database.
Improved fragmentation schemes for identifying functional groups.