Release Notes

BROOD v2.0

April 2010

This is a major rewrite of BROOD including a new database format, faster searching, a much larger database and a graphical interface. The graphical interface greatly simplifies selection of a molecular fragment for replacement and facilitates specification of constraints.

New Features

• BROOD now comes with a new graphical application, vBROOD, for setting up searches.
• Includes specification and graphical editing of color constraints. Pre-definied standard constraints and user-defined constraints are available.
• New database of more than 3.6 million, common, medicinal fragments.
• New database format for faster search times.
• Improved hitlist organization, including a hierarchy based on reduced graphs.
• Optimized analog molecule overlay.
• Allows incorporation of a protein structure for clash detection.
• Graphical interface allows designing of some physical properties.
• Assessment of synthetic accessibility of generated structures.
• Implementation of activity belief model for analog molecules.
• Includes a VIDA extension for ease of exploring results.
• 1-step database generation, including fragment generation and filtering, charge and property calculation, conformer generation, and buffered database creation.

BROOD v1.1.2

February 2009

This is a major bug-fix release for BROOD v1.1. This fix includes a major fix to the licensing system that allows BROOD to use licenses that expire in the year 2010 and later.

Release Notes:

1. Updated the license system to work with licenses that expire in 2010 and later.
2. BROOD installations now support having multiple versions and platform architectures in the same directory structure.

BROOD v1.1.1

August 2007

This is a minor bug-fix release for BROOD v1.1. This release includes a handful of fixes to bugs that have been reported over the past three months. Several of the most important bugs related to the -ET flag. We strongly recommend that anyone using electrostatic similarity should upgrade to this new version.

Release Notes:

1. Fixed major bug that caused molecules in the queryAnalog.build hitlist to be disconnected fragments when the -ET flag was true.
2. Fixed bug that allowed the electrostatic Tanimoto to still include the attachment score.
3. Fixed bug that failed to include the total electrostatic Tanimoto score to be recorded in the report file, even when all the components were present.
4. Added explicit hydrogens to the entire rebuilt molecule when the -build flag is used with 3D input.
5. Removed fragmented partial charges on fragments and built molecules before they are written as output.
6. Fixed counting error for the number of warnings reported in the information and log files.
7. Categorized and ordered the appearance of parameters in the auto-help.

BROOD v1.1

May 2007

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 electroctatic 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:

1. Improved conformers of constructed analog molecules to be as close to the original build molecule conformers as possible.
2. Added each score component to the report file as well as to the SDTags.
3. Added the frequency information to the SDTags.
4. Added bondOrder flag that by default requires attachment point bond order to be the same as those in the query fragment.
5. Changed color scoring from scaled-color to Tanimoto-color in order to prevent over-scoring of highly colored fragments.
6. Added shapeCut parameter to prevent very bad overlaps from appearing in hitlist when no good matches are found in the database.
7. Added attachCut parameter to eliminate fragments with poor attachmnet geometries regardless of how good their shape and chemical similarity is.
8. 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.
9. 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.
10. Improved documentation of hitlists and database generation.
11. Updated OEChem to include the ability to read SDTags from the .oeb formatted database file.
12. Added info file to CHOMP runs.
13. Added warnings when short hitlists are encountered.
14. Added fragment filtering progression and hitlist size to info file.
15. Cleaned up the column ordering in the report file.
16. Properly handle cases with more than three attachment points.
17. Changed :option: -sdtag default from “true” to “verbose”.
18. Imporved reporting of early initialization problems.

BROOD and CHOMP Bug Fixes:

1. Built analog molecules are now aligned with the input build molecule.
2. Fixed bug that caused the query fragmnet to be moved before the search began and never replaced.
3. Fixed bug that prevented the proper behavior of the :option: -build flag in conjunction with the :option: -ET flag.
4. Corrected bug related to the :option: -fileCharge flag.
5. Fixed query fragment to build molecule matching bug related to differing aromaticity models.
6. Fixed two CHOMP bugs that prevented the :option: -smarts flag from working properly.
7. Removed potential for double-counting non-default attachment scale parameter when used with the :option: -ET flag.
8. Fixed memory leak in large hitlist management system.

Database Features:

1. Improved database fragment content to include common fragments of all sizes up to 15 heavy atoms (or 350 MW).
2. Generate, use and attach fragment frequency information to each fragment.
3. Developed new methods for filtering fragments rather than filtering whole moelcules before fragmentation.
4. Eliminated primary-fragment database.
5. Added simple chemical complexity filters.
6. Improved perception of anionic hydrogen-bond perception.

Database Bug Fixes:

1. Fixed partial charge errors that occurred on some attachment point methyl groups.
2. Fixed polar-proton partial charge error.
3. Removed duplicate fragments.
4. Fixed ring-opening bug that fragmented most aliphatic heterocycles, thus preventing them from occuring in the original database.
5. Fixed branching bug that prevented some unusual branching patterns from occuring in the database.
6. Improved fragmentation schemes for identifying functional groups.

BROOD v1.0.1

May 2006

This version vixes several minor bugs.

BROOD v1.0

April 2006

This is the first official release of the bioisostere search program BROOD. This release is a significant overhaul of the beta2 release. It includes dramatic feature enhancements, bug fixes and optimizations. Most notable are improvements in the manner in which fragments are ranked and addition of electrostatic similarity. Further, this release has been applied to many bioisostere examples from the medicinal chemistry literature that have helped to refine its performance. Finally, this release makes generation of a custom fragment database much easier.

Release Notes:

1. Fixed major bug in initial fragment orientation.
2. Added electrostatic similarity measure
3. Significantly refined the evaluation functions for ranking bioisosteres.
4. Added the ability to replace the query fragment with bioisosteric fragments in an initial molecule.
5. Added separate handling of query analog fragments to avoid filling the hitlists with obvious answers.
6. Allow user specified partial charges and query conformer.
7. Allow user defined scaling of the contribution to similarity resulting from the attachment points.
8. Added the ability to write intermediate hitlists during execution.
9. Allow user to limit results to ring fragments only.
10. Refinement of default fragment databases.
11. Execution speed optimizations.
12. Addition of two applications for generating a database of molecular fragments.

BROOD v0.9 beta 2

January 2006

This beta release of the bioisostere program includes several significant improvements despite coming soon after the first beta release. Most importantly, this release fixes a licensing bug, a best-overlay bug, an RMS sorting bug, and a hydrogen placement bug in the fragment library. New features include, improved sampling for fragments with a single attachment point and more complete SDTag data.

Release Notes:

1. Improved sampling and initial orientation of fragments with a single attachement point.
2. Incorporated color score file into the application.
3. Improved proton placement in the fragment library.
4. SDTag data now includes all the scores of a fragment.
5. Fixed RMS sorting bug.
6. Fixed best-overlay nan bug.
7. Resolved internal licensing problems.
8. Improved documentation of attachement point representation in SMILES and SDF file formats.

BROOD v0.9 beta 1

December 2005

This is the first public release of the bioisostere program. The primary purpose of this release is to garner feedback concerning the functional aspects of the scientific product. Critical questions to address include; does it work in prosepctive studies, are users satisfied with the fragment database, are the three types of bioisosteres incomplete, sufficent or overwhelming. This release has a minimal feature list, but should be stable and robust. While it is not exceptionally slow, it has not been optimized for speed nor has it been adapted to PVM or MPI.

New Features:

1. Multiconformer database of over 90 thousand unique molecular fragments generated from commercially avialable compounds.
2. Automatic 3D conformer generation for query fragments.
3. Automated generation of hitlists for geometric, chemical and balanced classes of bioisosteres.