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CHANGELOG

mmpdb 3.1 - 2023-11-28

Extended the "generate" command to handle 2-, and 3-cut transforms.

The generate --explain option now also explains why the search for a matching query or variable part passes or fails. This proved useful in determining that an expected fragmentation was instead being filtered.

The new --min-heavies-total-const-frag N fragmentation option specifies the minimum number of heavy atoms allowed in the constant part. The default value is 0.

Changed the fragdb schema version (in the "options" table) from 3 to 4 to support the new fragmentation option. Version 3 fragment databases are still supported, by min_heavies_total_const_frag to 0.

Added two indices and a SQLite pragma for the page size. Roche reports these improve analysis performance.

Fixed --from and --to support in proprulecat. These had been left behind in the migration to click from argparse for command-line processing.

mmpdb 3.0 - 2023-5-31

A large number of changes to merge three different development tracks and add new features.

The "fragments" file format has been replaced with a SQLite-based "fragdb" file format. This makes it much easier to develop tools to work on fragment data sets instead of processing a JSON-Lines file.

New functionality to create an MMP data set in a distributed compute environment. Some of the features are:

  • split a SMILES file into a set of smaller SMILES files
  • the default "fragment" file output is now based on the input name
  • fragment files can be re-partitioned by constant fragments:
    • the "fragdb_constants" file generates fragment information
    • the "fragdb_partition" create re-partitioned fragdb files
  • the default "index" file output is now based on the input name
  • there are tools to merge fragdb and mmpdb files into one

As a result, mmpdb can now handle significantly larger data sets.

Added support for Postgres for direct index database creation. (The new distributed compute tools require SQLite.)

Added a new "generate" command to apply 1-cut transforms to a structure, using MMP rules as a playbook.

Replaced the SHA256-based Morgan fingerprint signature with a canonical SMARTS representing the Morgan fingerprint environment. This is difficult to understand or depict, so also include a "pseudo" SMILES that can be parsed by RDKit (if sanitize is disabled) and drawn. The new environment fingerprint also include the SMARTS of its parent, that is, the SMARTS with a smaller radius.

Switched to 'click' for command-line parsing, removed the vendered version of the peewee ORM, and switched to a modern "pyproject.toml" project configuration with a setup.cfg which declares its dependencies.

mmpdb 2.2-dev (the GitHub development track)

The fragment and smifrag commands now support options for supervised fragmentation based on a specified set of R-group SMILES to use for the fragmentation. Multiple SMILES can be specified on the command-line using the --cut-rgroup argument, with one SMILES per argument, or using the --cut-rgroup-file argument with the name of an R-group file. The file must be formatted with one R-group SMILES per line.

All SMILES strings must contain a single wildcard atom ("*"), which indicates the attachment point. The wildcard atom must contain only one single bond to the rest of the R-group, and cannot contain charge, hydrogens, isotope, or other properties.

The SMILES strings are converted into a SMARTS pattern which matchs the SMILES exactly (each atom must have the same valence and hydrogen count, and the bond types must match). These SMARTS patterns are then merged into a single recusive SMARTS with two terms: the wildcard atom, single bonded to a recursive SMARTS term for each of the SMILES strings.

The new rgroup2smarts command can be used to process the R-group SMILES into SMARTS, as a way to examine the conversion process and verify that it works.

mmpdb 2.2 - 2019-01-11

This minor release contains improvements that help reducing the database size. Many transformations and associated statistics inside the database are unlikely to ever be used, since there are other transformations that will yield the same compounds. To accomplish this, three new options have been introduced:

  • max-radius: The maximum radius can now be set on the command line during indexing. This was hardcoded in previous versions.

  • smallest-transformation-only: Some transformation scan be reduced to smaller transformations, for example p-Fluoro-phenyl >> p-Chloro-phenyl to Fluoro >> Chloro. If this flag is set during indexing, reducible transformations will not be written to the database. Note that this only setting reduces the number of transformations for a given pair. It does not completely remove a pair.

  • min-heavies-per-const-frag: For double- and triple-cuts, fragmentations are created where the constant parts can be very small down to a single atom. For example, if the fragmentation algorithm can generate a single-cut where the variable fragment is p-Fluorophenyl, it will also generate a double cut with phenyl as variable fragment and F as one of the constant pieces. The 'min-heavies-per-const-frag' option can be used during fragmentation to eliminate multiple cuts where one of the constant fragments is very small. If this is set to 3 or 4, double- and triple cuts only happen at positions that would be considered real scaffolds changes in the middle of molecules. Note that in principle this option only reduces the number of pairs for a given transformation, effectively removing multiple-cuts where possible. There may be edge cases where pairs are completely removed, because the single cut transfers too many atoms. If you use this option, you may want to adjust the --max-variable-heavies option during indexing.

    The last '--smallest-transformation-only' and '--min-heavies-per-const 3' options together typically reduce the database size by ~ 70%.

mmpdb 2.1 - 2018-04-27

  • RDKit 2018_03_1 changed the SMILES output so wildcard atoms are represented with a * instead of [*]. mmpdb works with SMILES strings at the syntax level. Parts of the code expected only the old RDKit behavior and crashed or gave the wrong output for the new behavior. For example, the fragmentation algorithm raised an AssertionError saying:
  File "mmpdblib/fragment_algorithm.py", line 368, in make_single_cut
    constant_smiles_with_H = replace_wildcard_with_H(constant_smiles)
  File "mmpdblib/fragment_algorithm.py", line 302, in replace_wildcard_with_H
    assert smiles.count("[*]") == 1, smiles
AssertionError: *O

Version 2.1 now supports both ways of representing the wildcard atom and will work with RDKit releases from 2017 and 2018.

  • The tests are now included as part of the distribution.

  • mmpdb is available from PyPI using "pip install mmpdb"

  • A preprint of our paper is available from ChemRxiv. We received word today that JCIM has accepted it (after minor changes).

mmpdb 2.0 - 2017-08-15

First public release of mmpdb, an open-source matched molecular pair package designed to create and query MMP databases for big-pharma sized ADMET datasets.