mmpdb 2.2-dev1 - matched molecular pair database generation and analysis

Synopsis

A package to identify matched molecular pairs and use them to predict property changes.

Requirements

The package has been tested on both Python 2.7 and Python 3.6.

You will need a copy of the RDKit cheminformatics toolkit, available from http://rdkit.org/ . Apart from other standard scientific python libraries like scipy and numpy, this is the only required third-party dependency for normal operation, though several optional third-party packages may be used if available.

The matched molecular pairs are stored in a SQLite database. The APSW module from https://github.com/rogerbinns/apsw gives slightly better analysis performance than Python's built-in SQLite module.
The fragment file is in JSON Lines format (see http://jsonlines.org/ ). The ujson (https://github.com/esnme/ultrajson) and slightly slower cjson (https://github.com/AGProjects/python-cjson ) are both about 25% faster than Python 2.7's built-in 'json' module.
The "--memory" option in the index command requires the psutil module (see https://pypi.python.org/pypi/psutil/5.2.2 ) to get memory use information.

How to run the program and get help

The package includes a command-line program named "mmpdb". This support many subcommands. For examples:

"mmpdb fragment" -- fragment a SMILES file
"mmpdb index" -- find matched molecular pairs in a fragment file

Use the "--help" option to get more information about any of the commands. For example, "mmpdb fragment --help" will print the command-line arguments, describe how they are used, and show examples of use.

The subcommands starting with "help-" print additional information about a given topic. The next few sections are the output from

   % mmpdb help-analysis

If you wish to experiment with a simple test set, use tests/test_data.smi, with molecular weight and melting point properties in tests/test_data.csv.

Publication

An open-access publication describing this package has been published in the Journal of Chemical Information and Modeling:

A. Dalke, J. Hert, C. Kramer. mmpdb: An Open-Source Matched Molecular Pair Platform for Large Multiproperty Data Sets. J. Chem. Inf. Model., 2018, 58 (5), pp 902–910. https://pubs.acs.org/doi/10.1021/acs.jcim.8b00173

Background

The overall process is:

Fragment structures in a SMILES file, to produce fragments.
Index the fragments to produces matched molecular pairs. (you might include property information at this point)
Load property information.
Find transforms for a given structure; and/or
Predict a property for a structure given the known property for another structure

Some terminology: A fragmentation cuts 1, 2, or 3 non-ring bonds to convert a structure into a "constant" part and a "variable" part. The substructure in the variable part is a single fragment, and often considered the R-groups, while the constant part contains one fragment for each cut, and it often considered as containing the core.

The matched molecular pair indexing process finds all pairs which have the same constant part, in order to define a transformation from one variable part to another variable part. A "rule" stores information about a transformation, including a list of all the pairs for that rule.

The "rule environment" extends the transformation to include information about the local environment of the attachment points on the constant part. The environment fingerprint is based on the RDKit circular fingerprints for the attachment points. There is one rule environment for each available radius. Larger radii correspond to more specific environments. The "rule environment statistics" table stores information about the distribution of property changes for all of the pairs which contain the given rule and environment, with one table for each property.

1) Fragment structures

Use "smifrag" to see how a given SMILES is fragmented. Use "fragment" to fragment all of the compounds in a SMILES file.

"mmpdb smifrag" is a diagnostic tool to help understand how a given SMILES will be fragmented and to experiment with the different fragmentation options. For example:

  % mmpdb smifrag 'c1ccccc1OC'
                     |-------------  variable  -------------|       |---------------------  constant  --------------------
  #cuts | enum.label | #heavies | symm.class | smiles       | order | #heavies | symm.class | smiles           | with-H   
  ------+------------+----------+------------+--------------+-------+----------+------------+------------------+----------
    1   |     N      |    2     |      1     | [*]OC        |    0  |    6     |      1     | [*]c1ccccc1      | c1ccccc1 
    1   |     N      |    6     |      1     | [*]c1ccccc1  |    0  |    2     |      1     | [*]OC            | CO       
    2   |     N      |    1     |     11     | [*]O[*]      |   01  |    7     |     12     | [*]C.[*]c1ccccc1 | -        
    1   |     N      |    1     |      1     | [*]C         |    0  |    7     |      1     | [*]Oc1ccccc1     | Oc1ccccc1
    1   |     N      |    7     |      1     | [*]Oc1ccccc1 |    0  |    1     |      1     | [*]C             | C

Use "mmpdb fragment" to fragment a SMILES file and produce a fragment file for the MMP analysis. Start with the test data file named "test_data.smi" containing the following structures:

Oc1ccccc1 phenol
Oc1ccccc1O catechol
Oc1ccccc1N 2-aminophenol
Oc1ccccc1Cl 2-chlorophenol
Nc1ccccc1N o-phenylenediamine
Nc1cc(O)ccc1N amidol
Oc1cc(O)ccc1O hydroxyquinol
Nc1ccccc1 phenylamine
C1CCCC1N cyclopentanol

  % mmpdb fragment test_data.smi -o test_data.fragments

Fragmentation can take a while. You can save time by asking the code to reuse fragmentations from a previous run. If you do that then the fragment command will reuse the old fragmentation parameters. (You cannot override them with command-line options.). Here is an example:

  % mmpdb fragment data_file.smi -o new_data_file.fragments \ 
         --cache old_data_file.fragments

The "--cache" option will greatly improve the fragment performance when there are only a few changes from the previous run.

The fragmentation algorithm is configured to ignore structures which are too big or have too many rotatable bonds. There are also options which change where to make cuts and the number of cuts to make. Use the "--help" option on each command for details.

Use "mmpdb help-smiles-format" for details about to parse different variants of the SMILES file format.

The "--cut-smarts" option sets the SMARTS pattern used to determine which bonds to cut during fragmentation. Use "--cut-rgroups" or "--cut-rgroup-file" to cut R-groups specified by fragment SMILES.

2) Index the MMPA fragments to create a database

The "mmpa index" command indexes the output fragments from "mmpa fragment" by their variable fragments, that is, it finds fragmentations with the same R-groups and puts them together. Here's an example:

  % mmpdb index test_data.fragments -o test_data.mmpdb

The output from this is a SQLite database.

If you have activity/property data and you do not want the database to include structures where there is no data, then you can specify the properties file as well:

  % mmpdb index test_data.fragments -o test_data.mmpdb --properties test_data.csv

Use "mmpdb help-property-format" for property file format details.

For more help use "mmpdb index --help".

3) Add properties to a database

Use "mmpdb loadprops" to add or modify activity/property data in the database. Here's an example property file named 'test_data.csv' with molecular weight and melting point properties:

ID MW MP
phenol 94.1 41
catechol 110.1 105
2-aminophenol 109.1 174
2-chlorophenol 128.6 8
o-phenylenediamine 108.1 102
amidol 124.1 *
hydroxyquinol 126.1 140
phenylamine 93.1 -6
cyclopentanol 86.1 -19

The following loads the property data to the MMPDB database file created in the previous section:

  % mmpdb loadprops -p test_data.csv test_data.mmpdb

Use "mmpdb help-property-format" for property file format details.

For more help use "mmpdb loadprops --help". Use "mmpdb list" to see what properties are already loaded.

4) Identify possible transforms

Use "mmpdb transform" to transform an input structure using the rules in a database. For each transformation, it can estimate the effect on any properties. The following looks at possible ways to transform 2-pyridone using the test dataset created in the previous section, and predict the effect on the "MW" property (the output is reformatted for clarity):

  % mmpdb transform --smiles 'c1cccnc1O' test_data.mmpdb --property MW
  ID      SMILES MW_from_smiles MW_to_smiles  MW_radius  \ 
   1  Clc1ccccn1         [*:1]O      [*:1]Cl          1
   2   Nc1ccccn1         [*:1]O       [*:1]N          1
   3    c1ccncc1         [*:1]O     [*:1][H]          1

                               MW_fingerprint  MW_rule_environment_id  \ 
  tLP3hvftAkp3EUY+MHSruGd0iZ/pu5nwnEwNA+NiAh8                     298
  tLP3hvftAkp3EUY+MHSruGd0iZ/pu5nwnEwNA+NiAh8                     275
  tLP3hvftAkp3EUY+MHSruGd0iZ/pu5nwnEwNA+NiAh8                     267

  MW_count  MW_avg  MW_std  MW_kurtosis  MW_skewness  MW_min  MW_q1  \ 
         1    18.5     NaN          NaN          NaN    18.5   18.5
         3    -1.0     0.0          NaN          0.0    -1.0   -1.0
         4   -16.0     0.0          NaN          0.0   -16.0  -16.0

  MW_median  MW_q3  MW_max  MW_paired_t  MW_p_value
       18.5   18.5    18.5          NaN         NaN
       -1.0   -1.0    -1.0  100000000.0         NaN
      -16.0  -16.0   -16.0  100000000.0         NaN

This says that "c1cccnc1O" can be transformed to "Clc1ccccn1" using the transformation [*:1]O>>[*:1]Cl (that is, replace the oxygen with a chlorine). The best transformation match has a radius of 1, which includes the aromatic carbon at the attachment point but not the aromatic nitrogen which is one atom away.

There is only one pair for this transformation, and it predicts a shift in molecular weight of 18.5. This makes sense as the [OH] is replaced with a [Cl].

On the other hand, there are three pairs which transform it to pyridine. The standard deviation of course is 0 because it's a simple molecular weight calculation. The 100000000.0 is the mmpdb way of writing "positive infinity".

Melting point is more complicated. The following shows that in the transformation of 2-pyridone to pyridine there are still 3 matched pairs and in this case the average shift is -93C with a standard deviation of 76.727C:

  % mmpdb transform --smiles 'c1cccnc1O' test_data.mmpdb --property MP
  ID      SMILES MP_from_smiles MP_to_smiles  MP_radius  \ 
  1  Clc1ccccn1         [*:1]O      [*:1]Cl          1
  2   Nc1ccccn1         [*:1]O       [*:1]N          1
  3    c1ccncc1         [*:1]O     [*:1][H]          1

                               MP_fingerprint  MP_rule_environment_id  \ 
 tLP3hvftAkp3EUY+MHSruGd0iZ/pu5nwnEwNA+NiAh8                     298
 tLP3hvftAkp3EUY+MHSruGd0iZ/pu5nwnEwNA+NiAh8                     275
 tLP3hvftAkp3EUY+MHSruGd0iZ/pu5nwnEwNA+NiAh8                     267

  MP_count  MP_avg  MP_std  MP_kurtosis  MP_skewness  MP_min   MP_q1  \ 
        1 -97.000     NaN          NaN          NaN     -97  -97.00
        3 -16.667  75.235         -1.5     -0.33764     -72  -65.75
        3 -93.000  76.727         -1.5      0.32397    -180 -151.00

  MP_median  MP_q3  MP_max  MP_paired_t  MP_p_value
       -97 -97.00     -97          NaN         NaN
       -47  40.00      69       0.3837     0.73815
       -64 -42.25     -35       2.0994     0.17062

You might try enabling the "--explain" option to see why the algorithm selected a given tranformation.

For more help use "mmpdb transform --help".

5) Use MMP to make a prediction

Use "mmpdb predict" to predict the property change in a transformation from a given reference structure to a given query structure. Use this when you want to limit the transform results when you know the starting and ending structures. The following predicts the effect on molecular weight in transforming 2-pyridone to pyridone:

  % mmpdb predict --smiles 'c1cccnc1' --reference 'c1cccnc1O' \ 
            test_data.mmpdb --property MP
  predicted delta: -93 +/- 76.7268

This is the same MP_value and MP_std from the previous section using 'transform'.

  % mmpdb predict --smiles 'c1cccnc1' --reference 'c1cccnc1O' \ 
            test_data.mmpdb --property MP --value -41.6

I'll redo the calculation with the molecular weight property, and have mmpdb do the trival calculation of adding the known weight to the predicted delta:

  % mmpdb predict --smiles 'c1cccnc1' --reference 'c1cccnc1O' \ 
            test_data.mmpdb --property MW --value 95.1
  predicted delta: -16 predicted value: 79.1 +/- 0

You might try enabling the "--explain" option to see why the algorithm selected a given transformation, or use "--save-details" to save the list of possible rules to the file 'pred_detail_rules.txt' and to save the list of rule pairs to "pred_detail_pairs.txt".

History and Acknowledgements

The project started as a fork of the matched molecular pair program 'mmpa' written by Jameed Hussain, then at GlaxoSmithKline Research & Development Ltd.. Many thanks to them for contributing the code to the RDKit project under a free software license.

Since then it has gone through two rewrites. Major changes to the first version included:

performance improvements,
support for property prediction
environmental fingerprints

That version supported both MySQL and SQLite, and used the third-party "peewee.py" and "playhouse" code to help with for database portability. Many thanks to Charlies Leifer for that software.

The second version dropped MySQL support but added APSW support, which was already available in the peewee/playhouse modules. The major goals in version 2 were:

better support for chiral structures
canonical variable fragments, so the transforms are canonical on both the left-hand and right-hand sides. (Previously only the entire transform was canonical.)

Copyright

License information

The software derives from software which is copyright 2012-2013 by GlaxoSmithKline Research & Development Ltd., and distributed under the 3-clause BSD license. To the best of our knowledge, mmpdb does not contain any of the mmpa original source code. We thank the authors for releasing this package and include their license in the credits. See LICENSE for details.

The file fileio.py originates from chemfp and is therefore copyright by Andrew Dalke Scientific AB under the MIT license. See LICENSE for details. Modifications to this file are covered under the mmpdb license.

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