| MetaSite user manual | ||
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Chapter 1. Overview
1.1. What is MetaSite?
MetaSite is a computational procedure to predict metabolism issues related to cytochrome-mediated reactions in phase I metabolism. Validation of the method has shown that the primary site of metabolism was found in the top three MetaSite predictions for more than 85% of the cases. Moreover, MetaSite provides the structure of the metabolites formed with a ranking derived from the site of metabolism predictions.
In addition to predicting the site of metabolism, the method also highlights the atoms in the molecule that contribute to the prediction (i.e. they help direct the molecule in the cytochrome cavity such that the site of metabolism is in proximity to the catalytic centre). Directly blocking the primary site of metabolism can risk creating an inhibitor of the cytochrome, or may negatively affect the activity or selectivity of the compound towards its therapeutic target. Modifying these contributing regions that most influence the site of metabolism can bypass both of these potential problems.
The MetaSite procedure is completely automated and does not require any user assistance. All of the work can be handled and submitted in a batch queue.
The basic concept of MetaSite is to compare the interaction patterns computed inside the protein with the 3D structure of the ligand. The information obtained from a user-friendly interface can be easily translated into decisions in the drug discovery process.
MetaSite suggests positions on ligand molecules which should be modified in order to avoid metabolic degradation or to promote the release of an active compound from a pro-drug molecule.
Superposition of molecules, training set, ab initio computation, or statistical analysis are not required. MetaSite runs both on workstations and personal computers and supports a large variety of operating systems.
MetaSite is specifically designed for:
In silico Metabolism predictions.
Prediction of the site of metabolism for different cytochromes.
Prediction of the atoms that contribute to the site of metabolism.
Metabolite identification.
Prediction of CYP3A4 mechanism based inhibition.
Comparison of the site of metabolism due to different cytochromes.
Identification of cytochrome isoform(s) responsible for the metabolism of substrates.
Considering chemical reactivity towards the oxidation.
MetaSite can be used for:
Automatic prediction of the site of metabolism for xenobiotics.
Metabolite identification.
Relative metabolite retention time prediction.
Lead optimization; suggesting the place in the molecule to be protected against metabolic degradation.
Lead optimization; suggesting the site for chemical modification in pro-drug strategy.
Lead optimization; suggesting the part of the molecule that can potentially produce mechanism based inhibition.
Working with large batches of molecules in a single run.
Generating useful quantitative description for the protein with reference to the reactive center.
Patent protection.
1.2. MetaSite features
Site of metabolism prediction for:
Predefined cytochromes: 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5
Any 3D cytochrome structure introduced by the user.
An ensemble of the most common cytochromes, as available in different organs, has been collected to produce a global prediction for: Liver, Skin, Brain, ...
Metabolite Identification and ranking.
Relative retention time prediction: metabolites are shown in a relative hypdrobic scale to compare with HPLC retention times.
Prediction models for CYP3A4 mechanism based inhibition.
Import from the most common file formats: MOL2, SDF and SMILES.
Influence of chemical reactivity in the cytochrome-mediated metabolism.
2D visualisation of the results.
Single or multiple view of the results.
Export in html format to facilitate sharing of the results.
Command line interface.
Automatic 2D -> 3D conversion.
Automatic generation of 3D conformers.
1.3. What MetaSite is not?
MetaSite is not a training set dependent method, a docking algorithm, or a force-field method, although it is strictly linked to the GRID methodology used to generate the 3D input Molecular Interaction Field maps for the protein description.
Furthermore, MetaSite is not a conformational analysis tool although it does use a minimization tool to produce conformers. MetaSite is not a statistical tool nor is it a semi-empirical or ab-initio method, or an QSAR or 3D-QSAR method either, and does not use QSAR models for the Site of Metabolism prediction (so it is not training set dependent).
1.4. Program citation.
The following citation is suggested when referencing the program:
1.5. Program organization
MetaSite implements both graphical and command-line interfaces. The main MetaSite window looks like this:
From top to bottom one can see: the menu bar, the toolbar and a set of tab pages.
The menu bar provides access to all of the functions in MetaSite. Users will most frequently access the File and Tools menus, where molecular data import operations and execution of prediction procedures are respectively located. The toolbar buttons therefore provide quick access to these menu commands.
The extensive area covered by the tab pages is also where most user activity will be focused. Each page provides a view on the data being analyzed and shows a distinct perspective.
The main pages are:
the Dataset view: provides a tabular representation of the substrates and associated data previously imported into the application.
the SoM Classic View: displays the results of the Site of Metabolism (SoM) prediction in a classical fashion (all details resulting from a SoM computation may be explored for a selected substrate/CYP pair).
the SoM Multiple View: a tabular representation of the Site of Metabolism prediction data, allowing visual comparison of the hot spot predictions on a set of substrates for different CYP isoform.
the Metabolites view: provides a detailed representation of the Metabolite ID results, focusing on one substrate/CYP pair at a time.
the Metabolites ID summary view: provides a tabular representation of the highest ranking metabolites for all of the compounds under analysis.
the MBI view: provides a tabular representation of the prediction of mechanism based inhibition character for all compounds analyzed.
MetaSite also implements a command-line interface, which is suitable for batch execution and integration into existing software infrastructures. The command-line execution is controlled by simple input scripts.
Detailed descriptions of both the graphical user interface and the command-line interface are provided in specific chapters of the user manual.
1.6. Limitations
The present version imposes no arbitrary limits to the size or to the number of molecules in the processed datasets. However, the hardware and, in particular, the amount of RAM memory available might impose a limit.
1.7. User's support
Molecular Discovery is committed to providing high quality user support to our customers. FAX and e-mail support is included in the price of the commercial licenses. Reduced price academic licenses grant no user support.
Please address all correspondence to
<support@moldiscovery.com>
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