Generative Structure Floe - Site selection (classic)

Category Paths

Follow one of these paths in the Orion user interface, to find the floe.

  • Generative/Analogs

  • Deprecated

Description

This floe provides methods to perform Generative Design alterations on the input lead molecule.

There are currently 5 methods: a custom method called Graft, Join, Matched Molecular Pairs (MMP), Sprout, and Trim.

Site Selection: This floe provides an option of designating a specific “site” for the analog transformations to occur on the single input molecule provided. The goal is to generate analogs involving changes at the specified site.

Input/Output molecules: Lead molecules will be transformed to analogs and saved to the output dataset on the output molecule field. For comparison, a new field is added to the output records that contains the original molecule, stored as a SMILES. The lead molecule is removed from the output records unless the input field name is different than the output molecule field.

Methods: You can select one or more of Graft, Join, MMP, Sprout, or Trim for examining the generative output, but at least one method must be selected. Methods that require an external index provide a default version for use. There are additional floes in this package that allow users to generate their custom Graft or MMP or indexes based on their own structures. Each method has tunable properties available on their respective cubes for additional control of the method’s activities: Graft – Graft Database and Graft Analogs; Join – Join Analogs; MMP – Filter Transforms and MMP Analogs; Sprout – Sprout Analogs; and Trim – Trim Analogs.

Graft: A fragment replacement algorithm that replaces single fragments sequentially from the lead molecule, preserving 80% of the original structure. A default fragment index is provided, or a user-generated index can be selected. The default index is based on tcams (malaria dataset), but other indexes may be available in the OpenEye Org stack data, or custom indexes can be generated from the Advanced Floes offerings.

Join: A method that uses provided pre-prepared reagents (with attachment site(s)) to join the reagent fragments to the specified site. Checking of the grafted group is performed to avoid labile or other unrealistic chemistry involving the joined group. If the prepared reagents being joined have >1 attachment point defined, the method selects the lowest numbered attachment point to make the connection to the input structure. An option is available to convert any other attachment points to implicit hydrogens, which can be suppressed. A default reagent set is provided based on the Topliss fragments.

MMP: A method that applies Matched Molecular Pair transformations from an internal default index or a user-generated index. The default index is a set of matched pairs derived from ChEMBL, but other indexes may be available in the OpenEye Org stack data, or custom indexes can be generated from the Advanced Floes offerings.

Sprout: A simplistic atom sprouting method that can sprout atoms at site(s) specified by the user.

Trim: A simple side-chain trimming editor that trims atoms from terminal sites on the input structure(s). After each atom is removed, the new terminal atom alpha to the deletion site is validated against the user-selected atom type, and deletion continues until the specified shell-depth is reached, or until no new terminal atoms are found or are valid.

Properties: Simple properties can be computed on the generated analogs; any, or none, of the properties can be selected for output.

Filtering: Molecule filtering of various types can either be applied to the generated analogs or disabled entirely.

Promoted Parameters

Title in user interface (promoted name)

Inputs

Query Input (ui_result): Draw a query, or select a record from an existing dataset and annotate a single contiguous attachment site for processing

  • Required

  • Type: fragment_input

Input Mol Field (in_mol_field): Name of the field containing the molecule(s) to be transformed

  • Type: field_parameter::mol

Outputs

Output Dataset (output): Output dataset for Generative Design analogs

  • Required

  • Type: dataset_out

  • Default: GenDesign_site_analogs

Output Mol Field (output_mol_field): Name of the field to contain the modified molecule(s)

  • Type: field_parameter::mol

Method Parameters

Select Generative Method (method): The generative method(s) to be used

  • Required

  • Type: string

  • Default: [‘Graft’, ‘Join’, ‘Matched Molecular Pairs’, ‘Sprout’, ‘Trim’]

  • Choices: [‘Graft’, ‘Join’, ‘Matched Molecular Pairs’, ‘Sprout’, ‘Trim’]

Compute Molecule Properties (mol_props): Which molecule properties to calculate

  • Type: string

  • Default: [‘HeavyAtoms’, ‘MedChemInterest’, ‘MolComplexity’, ‘MolWeight’, ‘TPSA’, ‘XLogP’]

  • Choices: [‘HeavyAtoms’, ‘MedChemInterest’, ‘MolComplexity’, ‘MolWeight’, ‘TPSA’, ‘XLogP’]

Annotate Method (dedupe_annotate): Annotate output records with the method that generated each unique structure (On), or use a faster method that just deduplicates (Off)

  • Required

  • Type: boolean

  • Default: True

  • Choices: [True, False]

Filter Output (filtering): Enable molecule filtering of the generated analogs (see type specified by [Mol Filter])

  • Required

  • Type: boolean

  • Default: True

  • Choices: [True, False]

Mol Filter (mol_filter_type): Type of molecule filter to apply to the generated analogs

  • Type: string

  • Default: BlockBuster

  • Choices: [‘Lead’, ‘Drug’, ‘BlockBuster’, ‘BlockBuster+PAINS’, ‘PAINS’, ‘Custom’]

Advanced Method Parameters

Atom Limit (atom_limit): Only generate analogs for input molecules that have <= this limit on the number of heavy atoms

  • Type: integer

  • Default: 500

Check Valences (check_val): How to handle valence issues in generated analog structures

  • Required

  • Type: string

  • Default: reject

  • Choices: [‘reject’, ‘allow’, ‘fix’]

H-member Processing (hmem_processing): For input molecule selections, also process the equivalent H-member input structure

  • Type: boolean

  • Default: False

  • Choices: [True, False]

Site Selection Highlight (site_hilite): Attach an image identifying the submol site selection to each output record

  • Type: boolean

  • Default: True

  • Choices: [True, False]

Verbosity (verbosity): Sets the output logging verbosity

  • Type: string

  • Default: warning

  • Choices: [‘info’, ‘warning’, ‘error’, ‘debug’, ‘ddebug’]