OpenEye is pleased to announce the release of BROOD v3.0. This is a major update with many new features and enhancements: incorporation of crystallographic conformers; molecule strain calculation and relaxation; disconnected fragment joining; cyclization; source-molecule tracking; protein selectivity; property filtering; automated fragment selection and cluster exploration.
Same philosophy, improved software
At OpenEye, we believe that small molecules are best represented by two fundamental descriptors: shape and electrostatics. This representation of small-molecule similarity has proven useful again and again in ROCS high-throughput screening of available chemicals. In BROOD, we combine shape and electrostatic similarity searching with fragment replacement to generate novel molecules that are similar in 3D to the query.
BROOD replaces a fragment-sized part of a query molecule with fragments similar in shape and chemistry to generate analogs. The new analogs are built in 3D, compared to the conformation and, if available, protein-active site of the original molecule, and further filtered for an appropriate property profile. The final output molecules share some of the properties of the query, such as shape, but are distinct in other properties, generating insightful lead-hops or lead optimization suggestions for modelers and chemists to consider.
Custom fragment conformations
In prior versions all fragment conformations in BROOD’s databases came from OMEGA. The new version of BROOD’s database-generation program, CHOMP, allows users to incorporate fragment geometries from any 3D source. These could include conformations from experimental sources such as bound ligands or small-molecule crystal structures, or third-party conformational sampling software. CHOMP identifies molecular fragments, harvests fragment conformations from any 3D molecular file, carries out conformer duplicate-removal and writes the custom fragment conformations into the BROODdatabase.
When fragment replacement creates a novel molecule significant strain can be introduced at any new bond. Before proposing an analog molecule, BROOD relaxes internal strain without significantly distorting the overlap. In this release, we have significantly improved BROOD’s local strain-energy calculation using molecular mechanics optimization with a solvent model. In addition to calculating and reporting strain for each analog, BROOD allows users to control the maximum acceptable strain. Candidate molecules that cannot be successfully relaxed, relative to this threshold, are discarded.
Fragment joining and cyclization
New GUI elements have been added to facilitate joining two disconnected molecules or cyclization of two distant moieties within a molecule. BROOD identifies fragments that can connect chemically appropriate bond-vectors with a minimal number of atoms in an unstrained manner, similar to Paul Bartlett’s CAVEAT program [G. Lauri and P.A. Bartlett, CAVEAT: A program to facilitate the design of organic molecules, J Comput Aided Mol Des., 1994, 8, 51-66.]
Assisted ligand design
Experienced vBrood users can select fragments for replacement using a lasso. New users can conveniently select a query fragment from among the ones vBROOD automatically suggests. If users need a reminder of the current properties of the query molecule, they are displayed adjacent to the fragment selection tool.
Property filters now can now be set with both upper and lower bounds (previously only upper bounds were allowed).vBROOD includes a graphical interface specifically for assessing and adjusting the property filters for BROOD molecules. Users can interactively tailor the physical properties, predicted bioavailability, and molecular complexity of the new compounds.
Known molecule annotations
The latest version of BROOD annotates newly suggested analogs with similarity to known molecules. Whether users are interested in patented compounds, corporate compounds, or available compounds, BROOD can annotate each molecule in the output hit list with the most similar molecules from the compound collection. BROOD uses a 2D fingerprint similarity for this function.
Mapping fragments to source molecules
When a new analog molecule is suggested the source of the new fragment is now tracked. For the default BROODdatabase, the ChEMBL identifier for each source molecule is available. When a corporate collection is used to make a custom BROOD database, the corporate ID for the source molecule will be included in the BROOD output. Users of corporate databases (and, to a lesser degree, the default database) can identify other molecules that include the new fragment for synthetic information, off-target propensities, or project concurrence.
BROOD’s custom results navigation tool has been redesigned to be more intuitive, giving users an easy way to quickly explore the clustered and aligned analog molecules. The navigation tool gives improved feedback about molecular clusters and how to move from one cluster to another. A Favorites list allows users to quickly browse the results and select the best molecules to share with colleagues. BROOD’s navigation tool can display the molecular overlays in the context of an active site with automated display of the active-site residues, surfaces, and interactions.
Color annotation in results navigation
The fragments in BROOD’s results are now annotated with the color points designating donors, acceptors, positive and negative formal charges, and rings used to calculate their similarity to the query. These points can be visualized in theResults Viewer to help users understand the interactions that drove fragment selection.
Additional New features
This release of BROOD also adds support for several new Linux platforms as well as for multi-processing on Windows. It adds many user-requested features and fixes user-reported bugs. It includes important improvements to all five programs included in the BROOD suite as well as a substantial rewrite of the documentation. Additional features to these programs include:
- Auto-suggestion of fragments for replacement in query was added.
- Arbitrary strict stereo in query build has been reduced.
- Query building, searching, and results view has been streamlined.
- Cluster handling in hitlist filtering has been improved.
- 2D alignment of results viewing has been added.
- Upper and lower bound to filter properties has been added.
- Annotation of hitlist molecules with color atoms has been added.
- Cluster navigation has been improved.
- Cluster naming and manipulation has been simplified and improved.
- Viewer widget layout has been improved.
- Visibility of keyboard shortcuts and navigation has been improved.
- Protein selectivity has been added.
- A new fragment database derived from ChEMBL has been added. (Bento et al. 2014)
- Mapping of the top five source molecules onto each fragment has been added.
- Enumeration of stereochemistry to CHOMP has been added.
- Inconsistency between single-processor and MPI duplicate removal has been fixed.
- The user interface with clearer output and verbose output has been improved.
- Support for duplicate recognition and removal has been added.
- The ability to overwrite existing databases, if necessary, has been added.
BROOD is now available for download. Existing licenses will continue to work. To obtain a new license, please contact your account manager or email email@example.com
- Support for Ubuntu 14 was added.
- Support for RedHat v7 was added.
- Support for Mac OS X 10.9 and 10.10 was added.
- Mac OS X 10.6 and OS X 10.7 are no longer supported.
- This will be the last release for SuSe 11.
Watch the video "BROOD - Interchanging Parts" below featuring BROOD v3.0 presented by Dr. Gregory Warren, Senior Applications Scientist at OpenEye.
About OpenEye Scientific Software
OpenEye Scientific Software Inc. is a privately held company headquartered in Santa Fe, NM, with offices in Boston, Cologne, Strasbourg, and Tokyo. It was founded in 1997 to develop large-scale molecular modeling applications and toolkits. Primarily aimed towards drug discovery and design, areas of application include:
- Structure Generation
- Shape Comparison
- Fragment Replacement
The software is designed for scientific rigor, as well as speed, scalability and platform independence. OpenEye makes most of its technology available as toolkits - programming libraries suitable for custom development. OpenEye software typically is distributable across multiple processors and runs on Linux, Windows and Mac OS X.
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