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MMP Molecule Fragment (3rd Gen)

DeprecatedVernalis Chemistry Matched-Molecular Pairs extension for KNIME Workbench version 1.26.0.qualifier by Vernalis (R&D), UK

This node implements the Hussain and Rea algorithm (Ref 1) for finding Matched Molecular Pairs in a dataset. The user can specify the number of cuts to be made (1 - 10), and whether Hydrogens should be added.

The node implements the molecule fragmentation part of the process, enabling the fragmented molecule key-value pairs to be stored in a database for later recall or used directly in a subsequent pair-finding node.

A variety of fragmentation options are included:

  1. "All acyclic single bonds" - Any acyclic single bond between any two atoms will be broken. This is the most exhaustive approach, but can generate a large number of pairs (rSMARTS: [*:1]!@!=!#[*:2]>>[*:1]-[*].[*:2]-[*])
  2. "Only acyclic single bonds to rings" - Single acyclic bonds between any atoms will be broken, as long as at least one atom is in a ring (rSMARTS: [*;R:1]!@!=!#[*:2]>>[*:1]-[*].[*:2]-[*]).
  3. "Only acyclic single bonds to either rings or to double bonds exocyclic to rings" - single acyclic bonds between any atoms will be broken, as long as 1 atom is either in a ring, or in a double bond exocyclic to a ring, with the other end in the ring (rSMARTS: [*:1]!@!=!#[*;!R0,$(*=!@[*!R0]):2]>>[*:1]-[*].[*:2]-[*])
  4. "Only single bonds to a heteroatom" - Single acyclic bonds between any two atoms, at least one of which is not Carbon will be broken. Included to mirror C-X bond breaking chemistry prevalent in modern drug discovery (e.g. SNAr, Reductive Aminations, Amide formations etc. See Ref. 2) (rSMARTS: [!#6:1]!@!=!#[*:2]>>[*:1]-[*].[*:2]-[*])
  5. "Non-functional group single bonds" - This reproduces the fragmentation pattern used in the original Hussein/Rea paper (See footnote 24, Ref. 1), and also used in the RDKit Python implementation (Ref 3) (rSMARTS: [#6+0;!$(*=,#[!#6]):1]!@!=!#[*:2]>>[*:1]-[*].[*:2]-[*])
  6. "User defined" - The user needs to provide their own rSMARTS fragmentation definition, following the guidelines below.

Guidelines for Custom rSMARTS Definition

  • '>>' is required to separate reactants and products
  • Products require '[*]' to occur twice, for the attachment points (the node will handle the tagging of these)
  • Reactants and products require exactly two atom mappings, e.g. :1] and :2] (other values could be used).
  • The atom mappings must be two different values
  • The same atom mappings must be used for reactants and products
rSMARTS not conforming to these guidelines will be rejected during node configuration.

Optionally, when only a single cut is made, or connectivity tracking is enabled, context-fingerprints can be generated (one for each attachment point). The fingerprints generated are RDKit Morgan fingerprints, rooted at the attachment point(s) of the fragment key

The algorithm is implemented using the RDKit toolkit.

This node was developed by Vernalis Research . For feedback and more information, please contact knime@vernalis.com

1. J. Hussain and C Rea, " Computationally efficient algorithm to identify matched molecular pairs (MMPs) in large datasets ", J. Chem. Inf. Model. , 2010, 50 , 339-348 (DOI: 10.1021/ci900450m ).

2. S. D. Roughley and A. M. Jordan " The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates ", J. Med. Chem. , 2011, 54 , 3451-3479 (DOI: 10.1021/jm200187y )

3. G. Landrum " An Overview of RDKit " (http://www.rdkit.org/docs/Overview.html#the-contrib-directory) (section entitled 'mmpa')

Options

Select Molecule column
Select the column containing the molecules
Select Molecule IDs column
Select the column containing the molecule IDs
Select the Fragmentation Type
Select the required fragmentation option
User rSMARTS
The optional user-defined rSMARTS (see above for details)
Number of cuts
Select the number of cuts (1-10).

Advanced Settings

Treat no undefined chiral centres as chiral
Molecules with explicit chiral centres have newly created stereocentres given defined chirality. Those with only undefined possible stereocentres (e.g. CC(F)Br) will not have explicit stereochemistry assigned to newly created centres. Molecules with neither explicit or undefined stereocentres will have explicit chirality set at newly created centres if this option is selected, otherwise they will not be set.
Add H's prior to fragmentation
If checked, pairs with -H as a substituent will be included. This is recommended for when the number of cuts is 1, and is unavailable for other values
Remove Explicit H's from output
Explicit hydrogens will be removed from the output if selected (Only available when 'Add H's prior to fragmentation' is selected and enabled)
Filter by maximum number of changing heavy atoms?
If checked, the user can specify a maximum number of heavy atoms which are allowed to change between Matched Pairs
Maximum Number of variable heavy atoms
The maximum number of heavy atoms which are allowed to change between pairs
Filter by ratio of changing / unchanging atoms?
If checked, the user can specify a maximum ratio of changing to unchanging heavy atoms during fragmentation
Minimum ratio of changing to unchanging heavy atoms
The minimum ratio of changing to unchanging heavy atoms

Output Settings

Show number of changing atoms
The number of heavy atoms (not including 'A', the attachment point) will be included for Left and Right fragments
Show ratio of constant / changing heavy atoms
The ratio of constant / changing heavy atoms (not including 'A', the attachment point) will be included for Left and Right fragments
Add failure reasons to 2nd output table
If checked, the reason the molecule could not be fragmented is added to the second output table

Attachment Point Fingerprints

Add Attachment Point Fingerprints
If checked, then attachment point fingerprints are added. See above for further details. One column is added for each attachment point
Fingerprint Length
The number of bits in the fingerprints
Morgan Radius
The radius of the Morgan fingerprint
Use Bond Types
Should the bond types be included in the fingerprint generation
Use chirality
Should chirality be included in the fingerprint generation

Input Ports

Molecules for fragmenting

Output Ports

Key-value fragmentation pairs
Input rows for which the molecule could not be parsed in RDKit, or which could not be fragmented according to the options specified

Best Friends (Incoming)

Best Friends (Outgoing)

Installation

To use this node in KNIME, install Vernalis KNIME Nodes from the following update site:

KNIME 4.1
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