Introduction¶
BROOD is a lead generation tool designed to generate new and diverse compounds that satisfy isosteric and chemical feature constraints while also incorporating synthetic feasibility. Starting with a hit or lead molecule, BROOD generates bioisosteric analogs by replacing user-specified portions of the lead with fragments that have similar shape and electrostatics but with potentially novel connectivity and chemistry. Fragments and scaffold couplings are derived within the scope of a known chemical space, either user-specified or broadly relevant to medicinal chemistry (default BROOD database).
BROOD can also be used within the context of structure-based design if experimental or modeled cocrystal structures are available. Resulting BROOD analogs can be readily filtered and prioritized based on bioisosteric similarity, 2D chemical diversity, and 1D molecular properties. BROOD has multiple applications, including lead-hopping, side-chain enumeration, library design, and expansion of composition-of-matter patents.
The BROOD distribution comprises 2 programs as well as a script that can be run in conjunction with the OpenEye’s molecular visualizer, VIDA.
Applications¶
The BROOD distribution contains 3 applications:
Application to help find analog molecules to a lead molecule, by changing a portion of the molecules, where the new analogs have some desired properties, somewhat different than the lead molecule.
Graphical interface to the BROOD application.
Application to create a BROOD database by fragmenting molecules, filtering the fragments, generating 3D conformations, and organizing and indexing the fragments for rapid searching.
Utility Programs¶
The following utility programs are also included in this distribution:
BroodDBMerge: Utility to create a single database by merging two BROOD databases.
Installing the BROOD Database¶
Included in the BROOD product is a large database of fragments generated by fragmenting the ChEMBL molecular database [Bento-2014]. This database is available for download from db-downloads in a platform-independent format. For user convenience, the database is available in either ZIP or TAR.GZ format, though either file can be used on any platform.
The BROOD database is large (>5G) and will take 15-30 minutes to download with a good internet connection. When the download is complete, move the file to a convenient location and unpack (either unzip or untar/gzip) the database. The default BROOD database is a directory full of preorganized files that are optimized to make common BROOD searches execute quickly.
After unpacking the default database, set it as the default database:
Launch vBROOD either by double-clicking the icon or by using the command-line interface, depending on your platform.
To specify a database: under the Edit menu, select
->Edit Preferences....A preferences pop-up will open.Under the first line of the dialog, either type the path to your newly unpacked database or use the icon to open a file dialog that will allow you to browse to the database. In either case, specify the directory created in the unpacking process as the database rather than selecting one of the files contained in the database.