12.8 MetaQSAR - Management system for metabolic reactions

 

Index

12.8.1 Introduction

12.8.2 How to use MetaQSAR

        12.8.2.1 Reactions tab

        12.8.2.2 Papers tab

        12.8.2.3 Journals tab

        12.8.2.4 Search tab

                12.8.2.4.1 Search by similarity

                12.8.2.4.2 Search by property

        12.8.2.5 Statistics tab

12.8.3 Data structure

 

12.8.1 Introduction

Drug metabolism with its many enzymes and reactions is a key factor in early ADMET screens for the selection of promising drug candidates, but its success depends on the reliability of available tools. With a view to supporting metabolic screening, MetaQSAR was developed in order to collect and classify metabolic reactions.  The metabolic data can be retrieved from in-home experiments and/or meta-analysis of the literature and can be used for different kind of studies such as: analysis of the property space of the metabolic substrates, prediction of the metabolism and prediction of the production of toxic metabolites.

MetaQSAR plug-in offers a complete input system to manage and classify not only the metabolic reactions, but also the related substrate and products in term of molecular properties and 1D, 2D and 3D structures. To do that, MetaQSAR uses the multi-purpose VEGA ZZ database engine that offers different database engines (such as Access, MySQL, SQLite, SQL Server and more in general all ODBC data sources) able to manage in easy way a large number of molecules.

 

 

12.8.2 How to use MetaQSAR

MetaQSAR plug-in is a complete system for the management of metabolic reactions. To use it, you must show the main window, selecting Tools MetaQSAR in VEGA ZZ main menu.

 

MetaQSAR main window

 

At the top of this window, there is the menu bar whose functions are summarized in the following table:

 

Item levels

Shortcut Description
1 2 3
File New database - Ctrl+N Create a new empty MetaQSAR database. You can choose the format between Access 2003 (mdb) and Access 2007 (accdb). MetaQSAR supports also MySQL data sources, but in this case the best way is the use of a tool for the database conversion such as Access to MySQL tool. To connect to the database, you can use this data source file, that must be saved with .dsn file extension (e.g. MySQL MetaQSAR.dsn):

 

ODBC data source Comments
   
[ODBC] ODBC header
DRIVER=MySQL ODBC X.X Driver Take care to put the right driver version
UID=my_user User name of the MySQL account
PWD=my_password Password of the MySQL account
DFLT_BIGINT_BIND_STR=1 Specific MySQL option for MS Access compatibility
PORT=3306 TCP/IP port number of the server (default 3306)
DATABASE=metaqsar Database name
SERVER=server.domain.country TCP/IP address of the server

MySQL ODBC connectors for Windows are available here. Download and install x86 32 bit version (MSI installer).

To create a new MySQL user and to set the access policies to the database, click here.
 

Open database - Ctrl+O Open a MetaQSAR database that can be a file or an ODBC data source.
Close - - Close MetaQSAR window without disconnecting the database. if you re-open MetaQSAR (Tools MetaQSAR in VEGA ZZ main menu), you will find the graphic interface in the same status as when you closed it.
Edit Expert mode - - Checking this menu item, you enable the capability to edit all data. By default, MetaQSAR is protected from changes in order to avoid accidental modifications with the exception of the possibility to add new metabolic reactions.
Tools Calculate fingerprints All - Calculate the fingerprints of all molecules (substrates and products) in the database. When you perform this calculation for the first time, the Molecules table of the current database is modified adding three columns with a length of 255 characters (FpSim1, FpSim2 and FpSim3) in which the fingerprints are stored in Base64 format. So, to obtain the original fingerprint in binary format, you must join the three fields (FpSim1 + FpSim2 + FpSim3) and decode the resulting string using the Base64 scheme (the size of the fingerprint is 3736 bits, 467 bytes). These fingerprints are employed to search molecules by similarity (see Search tab).

When you select this menu item, a progress bar is shown at the bottom of MetaQSAR window and you can stop the calculation by clicking the Abort button.

Update - By this function, you can calculate the fingerprints only for the molecules for which the data is missing. This feature is useful when you added new molecules to the database and you need to calculate the fingerprints only for these ones.
Help Manual - Ctrl+H Show this manual.
About - - Show the copyright message.

 

Before to start to edit the metabolic reactions, you must follow these steps to prepare the data:

  1. Create a new MetaQSAR database (File New database). You can decide to create the database in the default directory (recommended choice) or in a different one. In the first case, it is much easier to open the database because it is automatically added to the pull-down menu at the bottom of the window every time that you start MetaQSAR.
  2. Open the empty database by pull-down menu (MetaQSAR database) or selecting File Open database in the main menu or clicking Open button button. In the last two cases, a file requester is shown.
  3. Add the substrate and products structures using Database explorer of VEGA ZZ. Practically, a MetaQSAR database is an enhanced version of a standard VEGA ZZ database, therefore you can use all VEGA ZZ tools to add single molecules or whole databases of molecules in different formats. Besides, the molecules can be added in any time to MetaQSAR and not only in this first preparative phase.

If you want to mange also the bibliographic data, you should:

  1. In Journals tab, add the publishers and the journals of the papers from which you extracted the metabolic reactions that you want to put in MetaQSAR.
  2. In Papers tab, add the papers in which are cited the reactions and link them to substrates/products.

Now you are ready to operate MetaQSAR. In the main window, there are five tabs allowing you to choose the different operating modes of the tool:

 

In this tab, you can manage the reactions linking them to the substrate and classifying them according to the MetaQSAR rules.

This tab allows the bibliographic data to be managed. In particular, you can add new papers and link metabolic substrates/products to their bibliographic source.

In this tab, you can edit the publishers and the journals used to classify the papers.

MetaQSAR is not only a tool for data entry, but includes also features to retrieve data with some capabilities to analyze it. In particular, in this tab, you can search substrates/products by structural similarity with a query molecule, or by molecular properties.

This tab shows statistics on the database.

 

12.8.2.1 Reactions tab

In this tab, you can indicate not only which metabolic reactions can give each substrate but also which atoms are involved.

 

Reaction tab

 

To input a reaction into the database, you must follow these steps:

  1. Search for the substrate and select it. In the Search parameters box, you can search by substrate name (Name), by journal or year of the paper in which the substrate is cited (respectively Journal and Year fields) and by code of the paper (Paper code) which includes the substrate. The search by substrate name doesn't require the full name but only the first characters because the substrate list is automatically updated when you are typing. The search results are shown in the substrate list.

You can use also the wildcards for more complex searches, but you must remember that SQL wildcards differs from DOS/Linux ones:

SQL DOS/Windows Linux Description
% * * A substitute for zero or more characters.
_ ? ? A substitute for a single character.
[charlist] N/A [charlist] Sets and ranges of characters to match.

 

WARNING:

Linux have a different syntax: the characters must be comma separated.

 

e.g.

Linux: [a,b,c]

SQL: [abc]

 

The syntax for character ranges is the same: [a-c]

[^charlist]

or

[!charlist]

N/A [!charlist] Matches only a character NOT specified within the brackets. The syntax differences are the same explained above.

The search by Journal or Paper code works properly only if each molecule is correctly linked to its paper (see Papers tab).

When you click the substrate name in the result list with the left mouse button, both 2D and 3D structures are shown respectively in MetaQSAR (Preview box) and VEGA ZZ windows. If you show the context menu of Preview box (click with the right mouse button), you can copy the 2D sketch of the molecule (Copy menu item)  to the clipboard, copy the SMILES string to the clipboard (Copy SMILES) and print the 2D sketch.

More advanced searches and operations can be performed showing the context menu of the substrate list:

Item levels

Description
1 2
Find molecules with reactions Search for molecules whose metabolic reactions are already inserted in the database.
without reactions Search for molecules whose metabolic reactions are not yet inserted in the database.
with reaction notes Search for molecules whose metabolic reactions are already inserted with notes in the specific field.
Edit -

Enable the edit mode: by default this feature is disabled to avoid accidental changes in the database. When you enable it, Delete menu item becomes active and the background color of the substrate list changes from white to yellow. Moreover, clicking a substrate previously selected, you can rename it and change the Toxic/reactive flag. This special flag is useful to indicate if product  is a toxic and/or reactive species.

Delete - Delete the substrate structure and all data about it (structure, molecular properties, reactions and links with the papers).

 

WARNING:

Delete substrates only by MetaQSAR and not by Database explorer, because only the former guarantees the data integrity, removing the cross-references in other tables.

Selecting a substrate with metabolic reactions, the ID of the reactive atoms (Atoms column), the full reaction description (Raection), the metabolic generation (Gen.), the involved enzyme (Enzyme), the alternative enzyme that can catalyze the reaction (Alt. enzyme), a flag indicating if the reaction gives toxic products (Toxic prod.) and the notes (Notes) are shown in the list below the Preview box. If you click a reaction in this box by left mouse button, the involved atoms are highlighted in VEGA ZZ main window as small transparent spheres coloured by dark green and besides, the tree of the Reactions box is automatically expanded in order to show you the main class and the class in which the reaction is grouped.

  1. Choose the reaction in Reactions box. You can find the requested reaction expanding the hierarchical tree by clicking the small triangles with the left mouse button. By context menu, you can also expand/collapse selectively or not the main classes and the subclasses of reactions. When you found the reaction, select it by the left mouse button.
  2. Click one or more reactive atom in VEGA ZZ 3D view. The selected atoms are highlighted by a transparent dark-green sphere and their IDs are shown in the Reactive atoms field. If you picked wrong atoms, you can click Reset button button to reset the selection. If you are not sure of the atoms involved in the reaction, you can check Uncertain atom and click them in the 3D view. They will be highlighted in magenta (instead of dark-green) and indicated with a question mark after their ID in Reactive atoms.
  3. Click Add button to add the new reaction linked to the substrate. The list of the reactions of the selected substrate will be automatically updated. If the reactive atoms are wrong or missing, also in this  step you can change them: click Reset button button if needed, repeat the selection and then click the Change button.
  4. If you have to complete the entry with optional information, enable the edit mode showing the context menu of the reaction list and checking edit (the background color changes from white to light yellow). Now, you can change Atoms, Gen. (metabolic generation: 1, 2, 3+), Enzyme, Alt. enzyme (alternative enzyme involved in the reaction), Toxic prod. (change to Yes if the reaction gives toxic metabolites) and Notes columns of the list clicking the corresponding fields. To clear a field, select Empty field in the context menu.

If you have  to remove a reaction from a substrate, you must select the reaction clicking it and in the context menu, choose Delete. This operation is possible only in edit mode.

In both lists of substrates and reactions, as well as for all MetaQSAR lists, you can change the sorting mode clicking the column header with the left mouse button. For example, if if you click the Enzyme column for the first time, the list is sorted in ascending order by enzyme, but if you click it for the second time, it is sorted in descending order.

 

12.8.2.2 Papers tab

In this tab, you can manage the bibliographic resources adding new papers or editing them and linking substrates and products to their sources in which they are cited.

 

Papers tab

 

Here you can add new articles, filling the fields and clicking Add button in Add new paper box at the bottom of the window. The Journal combo-box is automatically updated with the data inserted in the Journals tab and only the short title is shown. Take care to define the paper code (Code field): 1) the maximum length of the code is 16 characters; 2) you can use your own convention, but you must use always the same. More in detail, in this example the papers are encoded as CYY_NNN where C is the journal ID (e.g. C = Chem. Res. Toxicol., D = Drug Metab. Dispos, X = Xenobiotica), YY is the publication year (e.g. 06 for 2006) and NNN is the progressive number.

All papers in the database are shown in the list at the left on the window and to simplify the view, you can filter them using the two pull-down menu at the top of the list. So, you can filter the paper by journal and/or year respectively with the leftmost and rightmost gadget.

The context menu of the paper list includes the features shown in the following table:

 

Item levels

Description
1 2
Find papers Orphan Filter the papers not yet linked to any molecule.
View - Show the paper of the selected item. This function works only if DOI  (Digital Object Identifier) is present and you have the subscription if the journal is not open access.
Edit - Enable/disable the edit mode. When you enable the edit mode, you can change all data of the selected item, just clicking them in the list. Moreover, you can also delete the whole record (see Delete item).
Delete - Remove the selected paper. This menu item is active only if the edit mode is enabled.
Refresh - Refresh the list of the papers. This function is needed only if another user changes the database, desynchronizing the list contents with the database.

If you have to link one or more substrates/products to a paper, you must follow these steps:

  1. Select the paper in the paper list. The filters and the sorting functions of the columns can help you in these phase. If the paper is missing, you can add it as explained above.
  2. Select the molecule that you want to link in list in the middle of the window. To find the molecule, you can use the Molecule filter at the top of the list that works in the same manner of the name filter in the Reactions tab. This list has its own context menu whose functions are summarized in the following table:

Item levels

Description
1 2
Find molecules Orphan Filter the molecules not yet linked to any paper.
Edit - Enable/disable the edit mode. When you enable the edit mode, you can rename and delete the selected molecule (see Delete item).
Delete - Remove the selected molecule. This menu item is active only if the edit mode is enabled.
  1. Click the Add button to make the link between molecule and paper. The linked molecule appears in the Molecules cited in paper list at the right of the window. Also this list has a custom context menu, whose functions are shown in the following table:

Item levels

Description
1 2
Edit - Enable/disable the edit mode. When you enable the edit mode, you can rename and delete the selected molecule (see Delete item).
Delete - Remove the selected molecule. This menu item is active only if the edit mode is enabled.
  1. If the link is wrong and you want to remove it, you must select the molecule and click the Remove button.

WARNING:

Don't use the Delete item of the context menu (it's enabled only in edit mode) because it delete the molecule and not the link !

 

12.8.2.3 Journals tab

This tab allows the publishers and the journals to be managed, data that is used for the right classification of the papers (see Papers tab).

 

Journals tab

 

To operate this tab, you must use the context menu (it's the same for both Publishers and Journals lists) whose functions are shown in the following table:

 

Item levels

Description
1 2
Open Web site - Show the Web site of the selected publisher or journal, if the Web site field is not empty. Remember that when you edit this field, you don't need to add http:// or https://  URL prefix.
Edit - Enable/disable the edit mode. When you enable the edit mode, you can add a new item and edit or delete a previously added one.
Add - Add a new empty item (function enabled only in edit mode). To edit the empty fields of the new item, just click them with the left mouse button.
Delete - Remove the selected item (function enabled only in edit mode).
Refresh - Refresh the list. As explained above, this function is useful if another user changes the database at the same time.

 

To add a new publisher or journal you must follow these steps:

  1. Enable the edit mode (check Edit in the context menu).
  2. Add a new empty item (select Add in the context menu).
  3. Edit the empty fields clicking them with the left mouse button.
  4. If you have to remove an item, select it and choose Delete in the context menu.

 

12.8.2.4 Search tab

MetaQSAR includes some tools to retrieve and analyze the metabolic data stored in the database. In particular, in this tab, you can search for substrates/products by structural similarity with a query molecule, or by molecular properties.

 

 

12.8.2.4.1 Search by similarity

Before to run a similarity search, you must calculate or update the fingerprints of all molecules included in the database, selecting Calculate Fingerprints in the main menu (for more details, click here).

Choosing By structure tab, you can search for substrates and related reactions, having a Tanimoto index greater than the specified value (see Similarity field). The input structure must be in SMILES format (see SMILES field) and can be edited typing manually the SMILES whose 2D sketch is shown in real time in the Query structure box.  If your knowledge of SMILES language is poor, you can build or download the query molecule in VEGA ZZ, using one of the tools included in the program (2D, 3D, IUPAC editors, optical structure recognition, PubChem downloader, etc), after that you can click the Get button to transfer the SMILES string from the current workspace to MetaQSAR.

 

Search by similarity

 

Clicking the Start button, the search begins and since the fingerprints are pre-calculated, is usually fast, nevertheless it can be stopped in any time clicking the Abort button shown in the status bar at the bottom of the window. The results are shown in Search result list: each line consists of the similarity index and the name of the substrate. Selecting a line, the substrate is shown as 2D sketch in Result structure box and in 3D in VEGA ZZ main window. Clicking the small triangle at the beginning of each line, you can show the reactions given by the substrate as code, generation number and description according to the MetaQSAR classification of the metabolic reactions. When you click the reaction, the involved atoms are highlighted in VEGA ZZ main window. The context menu of this output list includes interesting features as shown in the following table:

 

Menu item

Description
Collapse Collapse/expand the selected substrate to un/show the given metabolic reactions.
Expand
Collapse all Collapse/expand all substrates to un/show the given metabolic reactions.
Expand all
Export to Excel Export the results to Microsoft Excel.

 

12.8.2.4.2 Search by property

When you add a substrate to MetaQSAR, several molecular properties are calculated which can be used to perform searches. In By structure tab, you can build queries based on molecular properties adding the conditions in the table.

 

Search by properties

 

In each line of the table, you can add the Logical operator (and, or) , the molecular Property chosen by a pull-down menu, a mathematical Operator and the conditional Value. For a complete list of the properties, you can see the structure of the Molecules table (only the numerical properties are taken in account). If you add custom properties in Molecules table, they are added automatically to the pull-down menu.

To start the search, you must click the Search button, while to reset the query you can click the New button.

In the example shown in the above picture, 152 substrates giving 552 metabolic reactions are found according to a VirtualLogP value less than 2 and a mass value between 200 and 300 Daltons. As for the search by similarity, the results are shown in Search results box.

 

 

12.8.2.5 Statistics tab

 

This tab shows interesting statistical values of all data included in the database.

 

Statistics tab

 

In the window, there are four sections summarizing the statistics:

This part of the window shows generic statistics such as the number of substrates, metabolic reactions, enzyme classes, metabolic generations, reaction main classes, reaction classes, reaction subclasses, publishers, journals, papers, citations and publisher countries.

In this section, you can find the counts of the reactions according to metabolic generation (1, 2 and 3+) in which they are involved. Besides, the number of reactions giving toxic and/or reactive products is also shown.

This list shows the statistics on the enzyme classes involved in the metabolic reactions. In particular, for each class it is reported the number of reactions catalyzed as main and alternative enzyme, the relative percentages and the total amount of reactions with its percentage (main + alternative).

Here the statistics on main classes, classes and subclasses of metabolic reactions are shown. More in detail, for each main class (in red), class (in dark-blue) and subclass (in black) is reported the number of metabolic reactions and its percentage.

The context menu of this tab allows you to refresh the data (Refresh item) and export the statistics to Microsoft Excel (Export to Excel item) for a better analysis.

 

 

12.8.2 Data structure

MetaQSAR is a relational database containing both standard VEGA ZZ tables and specific ones to manage the metabolic reactions. The database is summarized in the following scheme in which the red arrows show the relationships between the tables.

 

Scheme of the tables included in MetaQSAR

 

As shown in this chart, the most important table is reactions that includes the information to classify the metabolic reaction. Different colours are used to group tables including homogeneous data tables: grey for the bibliographic information,  yellow for the enzymatic data, light blue for the substrate properties and their structures (1D, 2D and 3D), green for the reaction classification and pink for the management data.

Here, for each table, it is shown a short description, the fields, how they are defined (according to the SQL data types), the relationships between the tables and the default data included when an empty database is created:

 

Field Definition Description
CountryID INTEGER Primary key (autoincrement).
Country VARCHAR(50) Country name.
Compact VARCHAR(20) Short name of the country.

By default, in an empty MetaQSAR database are available two countries:

  1. United States of America (USA).
  2. United Kingdom (UK).

 

Field Definition Description
ClassID INTEGER Primary key (autoincrement).
Class VARCHAR(20) Enzyme class name.
EC VARCHAR(8) EC classification code.

MetaQSAR includes five main enzyme classes that can be changed and/or expanded by the user:

  1. Oxidoreductase
  2. Hydrolases
  3. Transferases
  4. Ligases
  5. Any

 

Field Definition Description
EnzymeID INTEGER Primary key (autoincrement).
Enzyme VARCHAR(100) Enzyme description.

By default, MetaQSAR includes 16 enzyme classes:

  1. Cytochromes P450
  2. Dehydrogenases
  3. FMO
  4. XO, AO
  5. Peroxidases
  6. Other reductases
  7. Other oxidoreductases or autooxidations
  8. Hydrolases
  9. UDP-Glucuronosyltransferases
  10. Sulfotransferases
  11. Glutathione S-transferases & subsequent enzymes/reactions
  12. Acetyltransferases
  13. Acyl-CoA ligases & subsequent enzymes
  14. Methyltransferases
  15. Other transferases or non-enzymatic conjugations
  16. Non-enzymatic hydrolyses or (de)hydrations

 

Field Definition Description
GenerationID INTEGER Primary key (autoincrement).
Generation VARCHAR(4) Generation description (1, 2, 3+).

Only three generations of metabolic products are considered by MetaQSAR, because the number of metabolites of 4th or more generation is negligible:

  1. First generation (1)
  2. Second generation (2)
  3. Third generation or more (3+)

 

Field Definition Description
ID INTEGER Primary key (autoincrement).
Group VARCHAR(50) Name of the user group.
Date DATE Creation date of the record.
Time TIME Creation time of the record.

 

Field Definition Description
TitleID INTEGER Primary key (autoincrement).
Title VARCHAR(10) Short name for paper encoding (e.g. CRT, DMD and XEN).
FullTitle VARCHAR(128) Full name of the journal.
Abbreviation VARCHAR(50) Journal title abbreviation.
EditorID INTEGER Editor ID (see publishers table).
URL VARCHAR(50) Web site URL of the journal.

By default, MetaQSAR includes three of the most important journal on metabolism, but others can be added by the user:

  1. Chemical Research in Toxicology
  2. Drug Metabolism and Disposition
  3. Xenobiotica

 

Field Definition Description
ID INTEGER Primary key (autoincrement).
MolID INTEGER ID of the substrate involved in the reaction shown in the paper  (see molecules table).
PaperID INTEGER ID of the paper including the reaction that involves the substrate (see papers table).
Date DATE Creation date of the record.
Time TIME Creation time of the record.

 

Field Definition Description
ID INTEGER Primary key (autoincrement).
Name VARCHAR(255) Molecule name.
IUPAC VARCHAR(255) IUPAC name.
Formula VARCHAR(50) Chemical formula.
Smiles VARCHAR(255) Smiles structure.
Inchi VARCHAR(255) InChI structure.
InchiKey VARCHAR(28) InChI key.
GroupID INTEGER Group ID (not used).
Cas VARCHAR(50) Chemical Abstract code.
Code VARCHAR(50) Auxiliary code (not used).
Angles INTEGER Number of bond angles.
Atoms INTEGER Number of atoms.
Bonds INTEGER Number of bonds.
Charge INTEGER Formal charge.
ChiralAtms INTEGER Number of chiral atoms.
Dipole REAL Dipole moment.
ExBnds INTEGER Number of bonds giving geometric isomers (E/Z).
FlexTorsions INTEGER Number of flexible dihedral angles (torsions).
FuncGroups VARCHAR(100) List of the functional groups. This string has the following format:
NUM_1 GRP_1 NUM_2 GRP_2 ... NUM_N GRP_N

where NUM is the number of functional groups of kind GRP. The functional groups are detected by the GROUPS.tem ATDL template (see the Data directory), as shown in the following table:

 

Group Description
COOH Carboxylic acid.
COOR Ester.
CHO Aldheyde.
CON2 Urea.
CON Amide.
OCOO Carbonate.
COCl Acyl chloride.
COBr Acyl bromide.
CNH Aldimine.
CNR Imine.
CO Ketone.
OCN Cyanate.
NCO Isocyanate.
NCS Tiocyanate.
CN Nitrile.
N1 Primary amine.
N2 Secondary amine.
N3 Tertiary amine.
N+ Ammonium salt.
NP Aromatic planar nitrogen.
NO3 Nitrate.
        
Group Description
NO2 Nitrite.
NNN Azide.
NO Nitrose.
NC Isocyanide.
OH2 Water.
OH Alchol.
PhOH Phenol.
OR2 Ether.
2O2 Peroxyde.
SO3H Sulfonic acid.
SO2 Sulfone.
SO Sulfoxide.
SH Thiol.
SR2 Thioether.
2S2 Disulfide.
PO4 Phosphate
P3 Phospine.
F Fluoride.
Cl Chloride.
Br Bromide.
I Iodide.

 

Gyrrad REAL Gyration radius  ().
HbAcc INTEGER Number of H-bond acceptors.
HbDon INTEGER Number of H-bond donors.
HeavyAtoms INTEGER Number of heavy atoms.
Impropers INTEGER Number of improper/pyramidal angles (out-of-plane).
Lipole REAL Lipophilicity moment.
Mass REAL Molecular weight (Daltons).
MassMI REAL Monoisotopic mass (Daltons).
Molecules INTEGER Number of molecules included in the record. This value is usually set to 1, but can be greater for salt, complexes, etc.
Ovality INTEGER Ovality is a form factor: it's close to 1 for spherical molecules.
Psa REAL Polar surface area (2).
Rings INTEGER Number of rings.
Sas REAL Solvent accessible area (2).
Sav REAL Solvent accessible volume (2).
Sdiam REAL Surface diameter: diameter of the equivalent sphere with the same surface of the molecule ().
Surface REAL Van der Waals surface area (2).
Torsions INTEGER Number of dihedral angles (torsions).
Vdiam REAL Volume diameter: diameter of the equivalent sphere with the same volume of the molecule ().
VirtualLogP REAL Log P calculated with Bernard Testa's method.
Volume REAL Volume (3).
Toxic INTEGER Toxicity flag: it can be 0 or 1 respectively for non-toxic or toxic molecules.
Date DATE Creation date of the record.
Time TIME Creation time of the record.
FpSim1 VARCHAR(255) These columns are optional and are added automatically when you calculate the fingerprints of the substrates/products included in the current database (see Tools Calculate fingerprints).
FpSim2 VARCHAR(255)
FpSim3 VARCHAR(255)

 

Field Definition Description
PaperID INTEGER Primary key (autoincrement).
Paper_Code VARCHAR(16) Paper ID. The convention used to encode the paper ID is:
CYY_NNN

where C is the journal ID (e.g. C = Chem. Res. Toxicol., D = Drug Metab. Dispos, X = Xenobiotica), YY is the publication year (e.g. 06 for 2006) and NNN is the progressive number.

JournaID INTEGER Journal ID (see journals table).
Year INTEGER Publication year.
Volume INTEGER Volume.
Issue VARCHAR(8) Issue.
FirstPage INTEGER First page.
LastPage INTEGER Last page.
Doi VARCHAR(32) Digital object identifier (DOI).
Date DATE Creation date of the record.
Time TIME Creation time of the record.

 

Field Definition Description
EditorID INTEGER Primary key (autoincrement).
Editor VARCHAR(50) Short name of the editor.
FullEditor VARCHAR(128) Full name of the editor.
Address VARCHAR(128) Address.
City VARCHAR(50) City.
Postal_code VARCHAR(32) Postal code.
State VARCHAR(50) State.
CountryID INTEGER ID of the country (see countries table).
URL VARCHAR(50) Web site URL (without http://).

 

Field Definition Description
ID INTEGER Primary key (autoincrement).
MainID INTEGER ID of the main class in which it's included (see reamain table).
ClassCode VARCHAR(8) Alphanumerical class code for easy class identification.
Description VARCHAR(128) Full description of the reaction class.

 

The 21 reaction classes are:

 

Num. Main class Class code Description
1 Redox 01 Oxidation of Csp3
2 02 Oxidation of Csp2 & Csp
3 03 -CHOH <-> >C=O -> -COOH
4 04 Various redox reactions of carbon atoms
5 05 Redox reactions of R3N
6 06 Oxidation of >NH, >NOH and -N=O // Reduction of -NO2, -N=O, >NOH, etc.
7 07 Oxidation to quinones or analogs // Reduction of quinones and analogs
8 08 Oxidation and reduction of S atoms
9 09 Redox reactions of other atoms
10 Hydrolysis & other 11 Hydrolysis of esters, lactones and inorganic esters
11 12 Hydrolysis of amides, lactams and peptides
12 13 Epoxide hydration
13 14 Other hydrolysis/hydration reactions // Non-enzymatic eliminations and rearrangements
14 Conjugations 21 O-Glucuronidations & glycosylations
15 22 N- and S-Glucuronidations // All other glycosilations
16 23 Sulfonations (O-, N-, ...)
17 24 GSH & RSH conjugations + sequels // GSH-mediated reductions
18 25 Acetylations & acylations
19 26 CoASH-Ligation followed by amino acid conjugations or other sequels
20 27 Methylations (O-, N-, S-)
21 28 Other conjugations (PO4, CO2, ...) // Transaminations

 

Field Definition Description
ID INTEGER Primary key (autoincrement).
MolID INTEGER ID of the molecule involved in the reaction (see molecules table).
ReaSubClassID INTEGER ID of the sub class of reactions in which the reaction is included (see reasubclasses table).
GenerationID INTEGER ID of the product generation (see generations table).
EnzymeID1 INTEGER ID of the main enzyme catalyzing the reaction (see enzymes table).
EnzymeID2 INTEGER ID of the alternative enzyme catalyzing the reaction (see enzymes table).
Atoms VARCHAR(50) Comma-separated list of the atoms involved in the reaction. For each atom is reported its ID of corresponding 3D structure (see structures table). For uncertain reactive atoms, the ID is followed by a question mark (?).
ProdID INTEGER ID of the molecule produced by the reaction (see molecules table, not yet used).
ProdActive INTEGER Boolean flag indicating if the product is active or nor (no more used, kept for MetaPies compatibility).
ProdReact INTEGER Boolean flag indicating if the product is reactive/toxic.
Notes VARCHAR(64) Field for generic notes.
Date DATE Creation date of the record.
Time TIME Creation time of the record.

 

Field Definition Description
ID INTEGER Primary key (autoincrement).
ShortDesc VARCHAR(32) Short description (used in the reaction tree of MetaQSAR plug-in).
Description VARCHAR(80) Full description.

The following table shows the default entries:

 

ID Short description Full description
1 01-09 Redox Redox reactions
2 11-14 Hydrolysis & other Reactions of hydrolysis and other non-redox functionalizations
3 21-28 Conjugations Conjugation reactions

 

Field Definition Description
ID INTEGER Primary key (autoincrement).
ClassID INTEGER Reaction class ID including this subclass (see reaclasses table).
MetaPieID INTEGER MetaPiesID (no more used).
Description VARCHAR(200) Reaction class description.

By default, a MetaQSAR database includes 101 reaction subclasses in this table as shown below:

 

Num. Main class Class Subclass code Description
1 Redox 01 Oxidation of Csp3 01 Hydroxylation (or other oxidations) of isolated Csp3
2 02 Hydroxylation (or other oxidations) of C alpha to an unsaturated system (>C=CC=O, -CN, aryl)
3 03 Hydroxylation (or other oxidations) of Csp3 carrying an heteroatom (N, O, S, halo) (including subsequent dealkylation, deamination or dehalogenation)
4 04 Dehydrogenation of >CH-CH< to >C=CCH-N< to >C=N- (incl. >C=N+<)
5 05 Other Csp3 oxidations (organometallic dealkylation, C-C cleavage, etc)
6 02 Oxidation of Csp2 & Csp 01 Oxidation of aryl compounds to epoxides, phenols or other metabolites
7 02 Oxidation of azaarenes to lactams or other metabolites
8 03 Oxygenation of >C=C< bonds to epoxides or other metabolites
9 04 Oxygenation of -C-CC-H and -C-CC-C- bonds
10 03 -CHOH <-> >C=O -> -COOH 01 Dehydrogenation of -CH2OH groups to -CHO and of >CHOH to >C=O
11 02 Hydrogenation of -CHO to -CH2OH and of >C=O to >CHOH
12 03 Oxidation of -CHO to -COOH
13 04 Reduction of arene and alkene epoxides
14 04 Various redox reactions of carbon atoms 01 Oxidative decarboxylation
15 02 Reductive dehalogenations
16 03 Reduction of arene and alkene epoxides
17 04 Other C reductions, e.g. of >C=C< to -CH2-CH2-
18 05 Redox reactions of R3N 01 Oxidation of tertiary alkylamines and heterocyclic amines to N-oxides or other metabolites
19 02 Oxidation of tertiary arylamines, azaarenes and azo compounds to N-oxides oxides or other metabolites
20 03 Reduction of N-oxides
21 06 Oxidation of >NH, >NOH and -N=O // Reduction of -NO2, -N=O, >NOH, etc. 01 Hydroxylation of amines to hydroxylamines or intermediates
22 02 Hydroxylation of amides to hydroxylamides
23 03 Oxidation of primary hydroxylamines to nitroso compounds or oximes (incl. spontaneous dismutation), then to nitro compounds
24 04 Reduction of hydroxylamines and hydroxylamides (incl. spontaneous dismutation)
25 05 Reduction of nitroso compounds and oximes to hydroxylamines
26 06 Reduction of nitro compounds to nitroso compounds
27 07 Other N-oxidations (1,4-dihydropyridines, etc)
28 08 Other N-reductions (e.g. azo compounds to hydrazines, hydrazines to amines, reductive N-rings opening)
29 07 Oxidation to quinones or analogs // Reduction of quinones and analogs 01 Oxidation of diphenols to quinones
30 02 Oxidation of amino- and amido-phenols to quinoneimines or quinoneimides, resp.
31 03 Oxidation of cresols and analogs to quinonemethides
32 04 Other oxidations of phenols and amines (dimerization, quinone-like metabolites, etc)
33 05 Reduction of quinones and analogs
34 08 Oxidation and reduction of S atoms 01 Oxidation of thiols to sulfenic acids or disulfides
35 02 Oxygenation of sulfenic acids to sulfinic acids, and of sulfinic acids to sulfonic acids
36 03 Oxygenation of sulfides to sulfoxides, and of sulfoxides to sulfones
37 04 Oxygenation of thiones (>C=S) or thioamides to sulfines, and of sulfines to sulfenes
38 05 Oxidative desulfurations of >C=S to ketones, and of -P=S to -P=O groups
39 06 S-Oxygenations of disulfides, thiosulfinates (-SO-S-), alpha-disulfoxides (-SO-SO-) and thiosulfonates (-SO2-S-)
40 07 Reduction of disulfides to thiols
41 08 Reduction of sulfoxides to sulfides
42 09 Other S-reductions
43 09 Redox reactions of other atoms 01 Oxidation of silicon, phosphorus, arsenic and other atoms
44 02 Reduction of Se, P, Hg, As and other atoms
45 Hydrolysis & other 11 Hydrolysis of esters, lactones and inorganic esters 01 Hydrolysis of alkyl esters
46 02 Hydrolysis of aryl esters
47 03 Hydrolysis of anionic and cationic esters
48 04 Hydrolysis of linear and cyclic carbamates (>N-CO-OR') and carbonates (RO-CO-OR')
49 05 Hydrolysis of acyl -glucuronides or other acylglycosides
50 06 Reversible hydrolytic opening of lactone rings
51 07 Hydrolysis of thioesters (RCO-SR' and RCS-SR') and thiolactones
52 08 Hydrolysis of esters of inorganic acids (nitrates, nitrites, sulfates, sulfamates, phosphates, phosphonates, etc)
53 12 Hydrolysis of amides, lactams and peptides 01 Hydrolysis of alkyl and aryl amides [alkyl-CO-N< and aryl-CO-N<]
54 02 Hydrolysis of anilides [aryl-N-CO-C~], hydrazides [-CO-NHNN-CO-N<]
55 03 Hydrolysis of lactams, cyclic imides and cyclic ureides
56 04 Hydrolysis of peptide bonds
57 13 Epoxide hydration 01 Hydration of arene and alkene oxides
58 14 Other hydrolysis/hydration reactions // Non-enzymatic eliminations and rearrangements 01 Hydrolysis of glucuronides and other glycosides (including N- and S-glycosides)
59 02 Other ether hydrolyses (benzhydryl ethers, acetals, etc)
60 03 Hydrolytic cleavage of C=N bonds (in imines, hydrazones, imidates, amidines, oximes, oximines, isocyanates, etc), and of CN bonds (nitriles). Double bond hydration
61 04 Hydrolysis of linear Mannich bases (N-, O- and S-Mannich bases) and cyclic Mannich bases (imidazolidines, oxazolidines, etc)
62 05 Hydrolytic opening of other ring systems (1,2-oxazoles, etc)
63 06 Hydrolytic dehalogenations
64 07 Substitution reactions (by H2O, halide, etc) in complexes of Pt or other metals (with elimination of halide or other ligands)
65 08 Bond order increases by elimination of H2O or RSH or other Nu-H
66 09 Cyclizations by intramolecular nucleophilic substitution (with elimination of amine, phenol, halide or H2O)
67 10 Any other non-redox, non-conjugation reaction
68 Conjugations 21 O-Glucuronidations & glycosylations 01 O-Glucuronidation of alcohols
69 02 O-Glucuronidation of phenols
70 03 O-Glucuronidation of carboxylic acids (including subsequent rearrangements)
71 04 O-Glucuronidation of hydroxylamines and hydroxylamides
72 22 N- and S-Glucuronidations // All other glycosilations 01 N-Glucuronidation of linear and cyclic amines (including =N- in azaarenes)
73 02 N-Glucuronidation of amides
74 03 S-Glucuronidation of thiols and thioacids, C-Glucuronidation of acidic enols
75 04 Any conjugations with glucose or other sugars
76 23 Sulfonations (O-, N-, ...) 01 O-Sulfonation of phenols
77 02 O-Sulfonation of alcohols
78 03 Other reactions (O-sulfonation of hydroxylamines, N-sulfonation of amines, etc)
79 24 GSH & RSH conjugations + sequels // GSH-mediated reductions 01 Nucleophilic additions of glutathione (to a,-unsaturated carbonyls, quinones and analogues, isocyanates and isothiocyanates, epoxides, etc)
90 02 Reactions of glutathione addition-elimination (at C-X groups, acyl halides, halogenated olefins, etc)
81 03 Metabolic processing of glutathione conjugates up to thiols
82 04 Conjugation of glutathione with Hg, As, Pt, etc, compounds
83 05 Conjugations with other thiols (Cys, N-Ac-Cys, etc)
84 06 Reductions following glutathione conjugations
85 07 Radical scavenging by glutathione and other thiols
86 25 Acetylations & acylations 01 N-Acetylation of aromatic amines
87 02 N-Acetylation of hydrazines and hydrazides
88 03 Other acetylations (N-acetylation of alkylamines, O-acetylation, etc)
89 04 Reactions of acylation (formylation, formation of fatty acyl esters, etc)
90 26 CoASH-Ligation followed by amino acid conjugations or other sequels 01 Conjugation with glycine, glutamic acid, taurine and other amino acids or short peptides
91 02 Conjugation with carnitine
92 03 Formation of hybrid glycerides, conjugation with cholesterol or other sterols
93 04 Unidirectional chiral inversion of profens and analogues
94 05 Chain elongation by 2C, beta- or alpha- oxidation (loss of 2C or 1C, resp.), other sequels
95 27 Methylations (O-, N-, S-) 01 O-Methylation of catechols and other hydroxy groups
96 02 N-Methylation of exocyclic and endocyclic amino groups (including =N- in azaarenes)
97 03 S-Methylation of thiols
98 04 Methylation of metals and metalloids (Hg, As, etc)
99 28 Other conjugations (PO4, CO2, ...) // Transaminations 01 Reactions of phosphorylation
100 02 Non-enzymatic formation of hydrazones, binding of CO2 to form carbamates
101 03 Other reactions of conjugation, transaminations


 

Field Definition Description
ID INTEGER Primary key (autoincrement).
Structure BLOB Binary object including the 3D compressed structure in IFF/RIFF format.

 

Field Definition Description
Key VARCHAR(16) Name of the data key.
Value VARCHAR(32) Key value.

Possible keys are:

 

Key Description
3DComp Compression algorithm used to store the 3D structures (see structures table).
3DFormat File format used to store the 3D structures (see structures table).
MetaQSAR This optional key can assume the value of 1 if the database includes the MetaQSAR tables or 0 if not. It it's missing, is a normal VEGA ZZ database.