BROOD - 3D Fragment Replacement

Description

BROOD - 3D Fragment Replacement 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, based on the specified Brood Fragments Database.

The default Brood Fragments Database Collection named ‘brood-database-chembl-xxx’ is available in organizational data, where xxx is a version number.

The query defines the portion(s) of the molecule that BROOD acts on, and it can be provided in one of two ways: sketched interactively in the Query Sketcher, or supplied as one or more previously prepared BROOD queries. A query is required — the floe fails if none is provided. Prepared queries must be generated from the same parent molecule; supplying them lets you run BROOD on a chosen set of queries of interest rather than as a batch over many molecules.

When sketching, the Query Sketcher offers three selection options:

  • Select atoms to keep (automatic query generation): Select the atoms to preserve, and BROOD automatically generates the query from the remaining atoms and runs the floe. Multiple disconnected segments may be kept, and an empty selection is also valid. This option is supported only for the ROCS and ET score types.

  • Select atoms to replace (classic Brood query): Select the atoms to be replaced, and BROOD builds a query from that selection. To search with more than one query, add a separate Query Sketcher instance for each query and select a single segment in each; every sketcher contributes one query. This option is supported for all three score types (ROCS, ET, and LinkOnly).

  • Select atoms for linking/cyclization: Select two separate segments that BROOD should join through a linking or cyclization process. This option is supported for all three score types (ROCS, ET, and LinkOnly).

Build Secondary is a switch that can be turned on or off. When on, BROOD replaces multiple query regions within the same molecule simultaneously, producing combined, multi-fragment analogs. When off, each query region is replaced independently, producing single-fragment analogs.

Promoted Parameters

Title in user interface (promoted name)

Input parameters

Brood Database (collection): Brood database collection

  • Required

  • Type: collection_source

Query Sketcher (ui_result): (Optional) Dataset containing 3D molecule

  • Type: fragment_input

Brood Query (in_query): (Optional) Dataset containing Brood Query

  • Type: data_source

Design Unit (in_du): (Optional with sketcher) Dataset containing design unit

  • Type: data_source

Components to keep as the ‘protein’ (protein_mask): DU components to use as the ‘protein’.

  • Type: string

  • Default: [‘protein’, ‘nucleic’, ‘cofactors’, ‘other_ligands’, ‘other_cofactors’]

  • Choices: [‘protein’, ‘nucleic’, ‘ligand’, ‘solvent’, ‘metals’, ‘counter_ions’, ‘lipids’, ‘packing_residues’, ‘sugars’, ‘undefined’, ‘cofactors’, ‘excipients’, ‘polymers’, ‘post_translational’, ‘other_proteins’, ‘other_nucleics’, ‘other_ligands’, ‘other_cofactors’]

Output parameters

Save Query (save_query): Save query built using Sketcher

  • Required

  • Type: boolean

  • Default: False

  • Choices: [True, False]

Query output (data_out): Output for BROOD - 3D query

  • Required

  • Type: dataset_out

  • Default: Output - brood query

Output Dataset (out): Output dataset of successful calculations

  • Required

  • Type: dataset_out

  • Default: Output for BROOD - 3D Fragment Replacement

Failed Dataset (failed): Output dataset of failed calculations.

  • Required

  • Type: dataset_out

  • Default: Failed Output for BROOD - 3D Fragment Replacement

Brood settings

Maximum Hits (max_hits): Maximum number of desired hits

  • Type: integer

  • Default: 10000

Build Secondary (build_sec): In addition to primary hits (one query fragment replaced at a time), generate secondary hits that replace multiple query fragments at once

  • Required

  • Type: boolean

  • Default: True

  • Choices: [True, False]

Score type (score_type): Score type to be used for Overlay

  • Type: string

  • Default: rocs

  • Choices: [‘rocs’, ‘ET’, ‘LinkOnly’]

Shape Cutoff (shape_cut): Minimum acceptable shape tanimoto

  • Type: decimal

  • Default: 0.6

Ring Requirement (ring_only): Ring requirement between attachment points in fragment.-2: Ring of any size; -1: Exclude rings; 0: Ring agnostic,1-12: Ring of specified size

  • Type: integer

  • Default: -2

Maximum Local Strain (max_strain): Maximum local strain allowed in analogs

  • Type: decimal

  • Default: 6.5

Delta Strain (delta_strain): Whether to calculate strain relative to query molecule

  • Type: boolean

  • Default: True

  • Choices: [True, False]