Frequently Asked Questions





1.


In Transformer you can find information about the isoformes of the Cytochrome P450 enzymes and about drugs which interact with those enzymes. If your focus is on the enzymes, you can find information about drugs that interact with a particular isoform and known DNA sequence variations of a particular isoform. For each isoform you will find an interactive 3D structure and links to other websites for further information. Another feature of our website is an alignment-tool with which, you can align as many sequences as you want and add sequences of your own. If your focus is on a particular drug, you can look for information about the P450 enzymes which interact with this drug. An ATC-Tree allows you to look for a drug on the basis of its ATC-classification. Another feature of this database allows you to check whether two or more drugs interact with each other (Drug interaction-check). If you use our database, please cite us! Thanks.

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2.


To be able to use Transformer Java has to be installed on your computer.
If you experience any problems with the Network applet, please visit this site to test wether Java in general is working on your computer. Please make sure to use the newest version of Java.

If you don't have Java installed, please follow the installation instructions below:

1. Go to the Java page.
2. Click "Free Java Download".

Furthermore, we recommend Mozilla Firefox 18 or newer (download here), Microsoft Internet Explorer 8 or newer, Apple Safari 5 or newer and Google Chrome 27 or newer.

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3.


3.1

Prodrug is an inactive drug that is metabolized to its active form in the body. Usually principle advantages are better bioavailability, reduced side effects and higher selectivity for targets. Many prodrugs have to be activated by specific enzymes, for example CYPs. Therefore it is important to know the (pro-)drug-cyp interactions (inducing or inhibiting effects) to provide non-responding and toxicity. To make it easier to check all those interactions, the “cocktail-tool” was developed.

3.2

Metabolism in this context is the chemical modification or degradation of chemicals including drugs and endogenous compounds. Drugs usually undergo metabolism in human bodies. Especially the liver contributes to a large extent to drug metabolism. Generally there are two types of reactions which pass consecutively, phase 1 (mostly Cytochrome P450 enzymes (CYPs)) to create functional groups via oxidation and phase 2 (for example UDP-glucuronosyltransferase (UGTs)) to make compounds more hydrophilic. The aim of that procedure is a better excretion and detoxification.

3.2

Many drugs may increase or decrease the activity of various enzymes in a phenomenon known as enzyme induction and inhibition. This is a major source of adverse drug interactions since changes in enzyme activity may affect the metabolism and clearance of various drugs. For example, if one drug inhibits the CYP-mediated metabolism of another drug, the second drug may accumulate within the body to toxic levels, possibly causing an overdose. Hence, these drug interactions may necessitate dosage adjustments or choosing drugs which do not interact with the same enzymes.

3.2

The cell membrane is not permeable for most of drugs, other compounds and electrolytes. Therefore transporter ensures an exchange between the intra- and extracellular space. They span a helix through the membrane and form a hydrophilic pore in the otherwise so lipophilic barrier. There are different kinds of transporters, selective for their substrates and different in their mechanism of transport. Some need ATP or over take the energy from a gradient of concentrations. It is known that transporters can be working to full capacity, so the taken dose is a different than the absorbed one. If more than one drug has to be transported by the same transporter, a lower effect can be expected.
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4.


4.1

The website gives you insight of a huge Database of drug transforming enzymes and their interactions between each other. You can browse for Prodrugs,Drugs or Phase 1 or 2 Enzymes and Transporters at the appropriate buttons. At the Cocktail button you can create a drug cocktail and get interaction information.
If you have any questions, which are not answered in the FAQs, please feel free to contact us!


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4.2





4.2.1

The Universal Protein Resource (UniProt) is a comprehensive resource for protein sequence and annotation data. The UniProt ID is the primary (citable) accession number of a entry in this database.

UniProt Website


4.2.2

PDB stands for Protein Data Bank and provides 3D structures from proteins and nucleic acids. The PDB ID is the identification number for these structures in the PDB database.

PDB Website


4.2.3

Accession Numbers are stable and unique identifiers for proteins from UniProt. The numbers are build up by 6 alphanumerical characters. One entry in the UniProt Database can have more than one Accession Number due to merging two or more entries - here every number of the entries are kept, or if an entry is demerged.


4.2.4

Enzyme Commission Numbers are stable classifiers for enzymes. They dont specify enzymes but enzyme-catalyzed reactions. Enzyme Commission Numbers are published by the International Union of Biochemistry and Molecular Biology. The current edition contains 3196 specified enzymes.

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4.3


4.3.1

This page allows you to search for drugs and prodrugs with their substance names, ATC-code, CAS number or PubChem ID (CID). If the search was successful, you will get to the results, which give you detailed information about the drug, such as the IDs, the chemical structure and properties and the interacting enzymes which are displayed with their Uniprot ID and the references right next to it. For the prodrugs you will additionally find the activating enzyme and reaction and the active metabolite.





4.3.2

The Anatomical Therapeutic Chemical (ATC) Classification System is used for the classification of drugs, which is controlled by the WHO Collaborating Centre for Drug Statistics Methodology (WHOCC). This pharmaceutical coding system divides drugs into different groups according to the organ or system on which they act and/or their therapeutic and chemical characteristics. Each bottom-level ATC code stands for a pharmaceutically used substance in a single indication (or use). This means that one drug can have more than one code. On the other hand, several different brands share the same code if they have the same active substance and indications.



Below the search-box there is the ATC-Tree. For instance if you want to see detailed information of the drugs for "Cardiovascular System", just click on the underlined code: "C" and then chose for example "C05 – Vasoprotectives". Either you click on the circle in front of the Code to see more selection options, or you just click on the code and you come to a result page of all drugs in this group. If you click on the little "circle" you will see the subdivisions. In brackets are the numbers of the drugs we provide in each category.


4.3.3

The PubChem ID is the identification number of the PubChem database. This database provides information of chemical structures, substance information and their bioactivity. This page is maintained by the National Center for Biotechnology Information (NCBI).

NCBI website

4.3.4

The simplified molecular-input line-entry system is a short ASCII strings which reflects structures of chemical molecules. Out of that string, it is possible to construct two-dimensional or three-dimensional image/model with molecule editors.


4.3.5

CAS Registry Numbers is a numerical identification system for chemical elements, isotopes, organic and inorganic compounds, ions, organometallics, metals and nonstructural materials administrated by the Chemical Abstracts Service.


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4.4


4.4.1

Type in the "Cocktail" query several drugs and select them below. By clicking on “Get Interactions” the user attains to an interactive table, which includes enzymes (transporter, phase 1 and phase 2) in the first column, which interact with the drugs on top of the table. If more than one drug interacts via the same enzyme, these lines are colored yellow (2 interactions), orange (3), red (4) and dark red (5 or more). If the drug is metabolized or transported by the enzymes, it is displayed as a substrate (S). Other interactions might inhibit (Inh), or induce (Ind) the enzyme. Some boxes include, additionally, exclamation points. These refer to food interaction which might occur. To obtain the references of these interactions click on the respective field of the table.
Now the user can choose one the suggested indications via ATC-code, for what the drug is given, to receive specific alternatives (e.g. dexamethasone for systemic corticoid effect). By clicking on an enzyme, the user is led to detailed information of the enzyme, including IDs, chemical structures, properties, interactive Network Views and 3D structures, of all enzymes. Moreover, the EHL and the Q0 value are provided for many drugs. The Q0 value (extrarenal excretion) is colored green if the value is <0.3, because those drugs are excreted unchanged to a large extent.

Click here for a short tutorial.



4.4.2

The Cocktail tool displays the Q0 and elimination half-life (EHL) values to compare the pharmacological properties of drugs and their alternatives. Thereby, extrarenal fraction (Q0) value is able to predict whether a drug is primarily excreted unchanged via kidneys or metabolized and/or removed through another pathway. Thereby is (1- Q0) the fraction, which is removed unchanged via kidneys. High Q0 values stand for mainly metabolized drugs and/or kidney independent excretion. In order to prevent adverse side effects and toxic drug levels in diseased kidney patients the Q0 value should be taken into account to change the drug or adjust the dosage. The Q0 could also help to estimate the extent of CYP-drug interactions. Drugs with low Q0 values (<0.3) are excreted unchanged to a large extent and occupying the CYP system lesser. Their impact on interactions is lower than for drugs with higher Q0 values. Hence, consideration of Q0 values in finding alternative drugs is useful to reduce the interaction potential, if the function of kidneys is sufficient. However, high values do not necessarily mean more CYP reactions. Nevertheless, it provides a useful support to select the alternative drugs. The elimination half-life (EHL) of a drug is the time in which it looses one half of its activity. The longer the half-life, the longer it will remain in the human body.

4.4.3

The results are presented in a dynamic table where you will find your chosen drugs on the ordinate and the interacting enzymes on the x-axis. To see the Reference of these interactions click on the respective field of the table, but please cite us, too! By clicking on the Drug or the Enzyme it will lead to detailed information about the IDs, the chemical structure and properties. To get alternatives of the drugs you have to choose the indication via ATC-Code. For example Acetylsalycilic acid (ASS) has three different indications: A01AD05 (Stomatological Preparations), B01AC06 (Antithrombotic Agents), and N02BA01 (Other Analgetics and Antipyretics). To get an expedient alternative you need to select one of those indications and you can complete your alternatives interactivily.
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5


5.1

Transformer provides interaction networks for every enzyme. By clicking on a drug the drug targets will open. Hence, the user can expand the Networks to find more links, interactions and maybe new ideas of drug targets. Those Networks are based on Cobweb PMID: 21486937. To find the reference of the interaction, the user has to click on the edge and the PubMedIDs will be shown on the right side of the network.




5.2

Drag the pressed right mouse button to scroll around.
Drag the little circle in the scale "Zoom" left or right to zoom out or in.




5.3

Most of the information that you can find in Transformer was extracted from original publications via text-mining and manual validation. These publications (or at least their abstracts), can be found in the website of Pubmed. Other sources are well known databases, such as Drugbank and fachinfo. Every entry in our database has a link on the right side of the screen under "References", but please cite us, too!


5.4

The term Proteomics stands for a study of all proteins, which were expressed by a genome. This study includes the identification, their structure and functions (especially the physiological and pathophysiological function). Proteome stands thereby for the entire protein complement with all modifications caused by an organism. Specifically the word Proteomics is used for methods of studying proteins like the mass spectrometry and the protein purification. We used it for the "Enzyme Browse Tool" to search for specific properties.


5.5

The models for the CYP and phase 2 enzymes as well as for the transporter proteins were obtained from ModBase.

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