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Meteor Reasoning Methodologies

Meteor Nexus 3.0 contains three different methodologies for assessing the likelihood of observed metabolites. These are:

Absolute/Relative Reasoning - The original Meteor Nexus prediction methodology. Ideal for those who wish to have the maximum predictive coverage of biotransformations, to spot obscure metabolites not necessarily identified experimentally.

Static Scoring (Occurrence Ratio) - This methodology uses a pre-computed score for how likely a biotransformation is, based on experimental data, and orders the predicted metabolites according to this score.

Site of Metabolism (SOM) Scoring - Builds on the Static Scoring methodology by tailoring the score using experimental data for compounds that match the same biotransformation, have similar molecular weights and are chemically similar around the site of metabolism to the query compound.


View an infographic describing how Meteor Nexus predicts using these three methodologies.
 

Absolute/Relative Reasoning

When using the Absolute/Relative Reasoning methodology in Meteor Nexus, submitted structures are compared to the certified Meteor knowledge base.

Meteor Nexus then predicts the first generation metabolites by using:

  • Lipophilicity
  • The presence or absence of structural features
  • The relative likelihood of competing transformations

The prediction is generated by applying expert knowledge rules in metabolism to the data returned from the knowledge base.

Each metabolite is analysed to predict further metabolism and its level of likelihood is shown.

 

A workflow describing this methodology is available here.The results are displayed in an interactive tree graphic along with supporting data, such as the reasoning behind each prediction, biotransformation details and metabolite path. 

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Static Scoring

When a user processes a compound through Meteor Nexus using the Static Scoring methodology, any biotransformations that fire will be displayed in the order of their Static Score.

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All biotransformations in Meteor Nexus have been given a pre-defined Static Score which is displayed to users in the prediction. In order to work out these Static Scores, the metabolism database was used to assess how often a Meteor Nexus biotransformation actually occurs, versus how often a biotransformation could occur, resulting in the generation of an Occurrence Ratio for each biotransformation (Figure 1). The Occurrence Ratio was then multiplied by 1,000 to give a Static Score.

Users can control how many metabolites they are presented with by modifying the processing constraints associated with the methodology:

  • Top N threshold - the top N biotransformations are displayed and N can be determined by the user i.e. the user can request to see the N biotransformations with the highest Static Score.
  • Relative threshold - the biotransformations that are displayed are at or above a percentage of the maximum score i.e. the user can request to see only biotransformations that have a Static Score within a defined percentage of the biotransformation with the highest Static Score.

It must be noted that Static Scores do not represent quantitative information.

  

A workflow describing this methodology is available here

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Site of Metabolism (SOM) Scoring (with Molecular Mass Variance)

The Site of Metabolism (SOM) Scoring with molecular mass variance is now the default setting in Meteor Nexus.

The SOM methodology builds on the Static Scoring methodology by tailoring the score using experimental data for compounds (from the metabolism database) that match the same biotransformation, have similar molecular weights and are chemically similar around the site of metabolism.

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When a user processes a compound through Meteor Nexus using the Site of Metabolism Scoring methodology, any biotransformations that fire will be displayed in the order of their Site of Metabolism Score (Figure 2). Users can control how many metabolites they are presented with by modifying the processing constraints associated with the methodology:

  • Top N threshold - the top N biotransformations are displayed and N can be determined by the user i.e. the user can request to see the N biotransformations with the highest Static Score
  • Relative threshold - the biotransformations that are displayed are at or above a percentage of the maximum score i.e. the user can request to see only biotransformations that have a Static Score within a defined percentage of the biotransformation with the highest Static Score.

It must be noted that Site of Metabolism Scores do not represent quantitative information.

 

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Figure 2: A screenshot from Meteor Nexus 3.0 of Rotigotine in the results tree, the biotransformations are ordered in the table in terms of their score.


Take, for example, the case of caffeine, which can perform biotransformation 242 at two sites of metabolism (Figure 3).

  • The sites of metabolism that biotransformation 242 can occur at are calculated for caffeine.
  • The structure fingerprint for each of these sites of metabolism is then determined to a depth of 8 bonds.

The diagram below shows how this is done for methyl group number 2 of caffeine. The product shown is known as the major metabolite1, which Meteor predicts as having a higher score.

1) B. Testa et al. Biochemistry of Redox Reactions (Metabolism of Drugs and Other Xenobiotics), Academic Press, 1994

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Figure 3: Finding the Site of Metabolism for Caffeine

 

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Figure 4: Cyclosporine G has a large molecular weight and numerous sites of metabolism. Many example compounds will have matching sites of metabolism, but those that do not have a molecular weight within a particular percentage of the query compound are eliminated.

A detailed workflow, describing this methodology, is available for members here.

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