MMP Calculate Maximum Cuts (RDKit)

This node calculates the maximum number of cuts which a molecule can support with the given fragmentation method

A variety of fragmentation options are included:

1. "All acyclic single bonds" - Any acyclic single bonds between any two atoms will be broken. This is the most exhaustive approach, which 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. "Matsy (One atom in ring, or a non-sp2 C atom bonded to a non-C atom)" - This reproduces the fragmentation pattern used by NextMove's 'Matsy', i.e. single acyclic bonds between either a ring atom and any other atom, or a heteroatom bonded to a non-sp2 C atom, as described in the Matched Series paper (Ref 4) (rSMARTS: [$([#6!^2]-!@[!#6]),$([*;R]-!@[*]):1]-!@[$([!#6]-!@[#6!^2]),$([*]-!@[*;R]):2]>>[*:1]-[*].[*:2]-[*])
7. "Peptide Sidechains" - Acyclic single bonds from Cα to Cβ will be broken. C-H will only be broken for Glycine, and only when explicit H are present (both CH bonds will be broken in this case) (rSMARTS: [C;$(CC(=O)[O,N]);$(CN):1]-!@[$([C]-!@C(C(=O)[N,O])N),$([#1]-!@[CH2](C(=O)[N,O])N):2]>>[*:1]-[*].[*:2]-[*])
8. "Nucleic Acid Sidechains" - Acyclic single bonds in the anomeric position between the aromatic base N and sugar will be broken. The minimum requirement is N(Ar)CO(CO)CO to allow for open chain analogues (rSMARTS: [n:1]-!@[$(COC(CO)CO):2]>>[*:1]-[*].[*:2]-[*])
9. "User defined" - The user needs to provide their own (r)SMARTS fragmentation definition, following the guidelines below

Guidelines for Custom (r)SMARTS Definition
An rSMARTS is no longer required, but may be specified if preferred for backwards compatibility. If specified must comply with the following rules. Otherwise, simply a match for two atoms separated by a single, acyclic bond must be provided

• '>>' 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.

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. 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)

2. 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)

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

4. N. M. O'Boyle, J. Bostrom, R. A. Sayle and A. Gill, "Using Matched Molecular Series as a Predictive Tool To Optimize Biological Activity", J. Med. Chem., 2014, 57, 2704-2713 (DOI:10.1021/jm500022q)