is a knowledge based expert decision support tool for predicting the metabolic fate of chemicals in mammals.

Transcription

1 is a knowledge based expert decision support tool for predicting the metabolic fate of chemicals in mammals. Reference 08/15

2 Features and Benefits Summary Efficient Metabolite Structure Elucidation Early Screen for Toxic Metabolites The integrated links to Derek, Sarah and Vitic Nexus allow licensed users to screen predicted metabolites and intermediates for toxicity. As an unbiased computer program, Meteor can be extremely valuable for metabolite identification; particularly for identification of unusual or unexpected metabolites. Decision Support Tool Education and Training Tool Extensive and current information is provided in the biotransformation description, which can be used to improve personal knowledge and is also an excellent training tool for scientists who may be new to the drug metabolism field. To help prioritise chemicals for further development and to ensure that you haven't missed any metabolism, Meteor Nexus provides transparent predictions with extensive supporting data such as the most likely metabolites, details of the mechanism; including intermediates, comments, references and supporting examples. Customisation of Knowledge In house knowledge from past research can be incorporated into your own copy of Meteor and then easily accessed by your researchers. Using the knowledge base editor tools, custom biotransformations, knowledge-based rules, references and supporting examples can be added to enhance the predicted results. Consensus Prediction Using the integrated SMARTCyp model or mass spectrometry data, Meteor allows you to be confident in the prediction by offering a consensus on multiple information sources.

3 What can Meteor do for you? Bringing current knowledge of metabolic biotransformations to your fingertips, Meteor Nexus is suitable for use in all stages of drug/compound discovery. Who uses Meteor? Meteor is used across a wide range of industry sectors, but most notably within pharmaceutical and biotech pharma and generics companies, regulators, government agencies and academia. Direct access to in silico tools 'Derek Nexus', 'Sarah Nexus' and 'Vitic Nexus' Prediction based on expert rules that account for physicochemical and structural properties CYP450 mediated metabolites include a SMARTCyp prediction; showing the 3 most likely points of metabolism Results include metabolism of metabolites and generation of suggested metabolites; not just identification of points of metabolism About the knowledge base Aldehyde Oxidase Abiotic or unknown enzymology Flavin Monoxygenase Other Phase I Cytochrome P450 Results can be filtered on various parameters including structure, nominal mass and mass defect Figure 1 The major enzyme classes represented in the Meteor biotransformation dictionary.* Phase II Detailed expert commentary, supporting examples and literature are detailed in the biotransformation details Biotransformation library includes Phase I and II metabolism for CYP and non CYP processes * Figures correct for knowledge base M2012KB as used in Meteor Nexus 1.5. Figure 2 The Meteor Nexus results display contains a wealth of information to allow for effective decision making.

4 How is Meteor used? The Use Of Meteor For Improved Efficiency And Accuracy Drug metabolism and pharmacokinetic (DMPK) departments are seeking ways to automate the process to improve efficiency and accuracy. The process followed by one Meteor user is detailed in figure 3. The Use Of Meteor For Unusual Metabolism Some Meteor users reserve use of an in silico prediction tool for cases where there is evidence of unusual metabolism, for example where an unusual biotransformation occurs where there is no precedence for it, or the biotransformations occur in an unusual combination or order. In this instance, Meteor is used with an absolute reasoning level of improbable, with the aim of providing a very large resulting prediction. The results can then be searched to identify the unusual biotransformation(s) and view the suggested biotransformation pathway associated with its generation. Compound Meteor report generated Tree of predicted metabolites generated. Tree includes details such as the accurate mass of each predicted metabolite. Figure 4 The ring contraction of 2,2,6,6 Tetramethylpiperidines to 2,2 Dimethylpyrrolidines is an example of a biotransformation displaying unusual chemistry The Use Of Meteor For Metabolite Elucidation Via Mass Defect Analysis Figure 5 The inclusion of prototype biotransformations in the knowledge base, is of particular use in this case, as they represent a way of expressing metabolism where there is limited literature data available, but has some precedence in terms of chemistry. The Use Of Meteor With Mass Spec Software MS vendor empirical list Acquisition method is directed by the results from Meteor Nexus and the empirical list provided by MS vendors. Acquisition of samples is data driven. If an ion of predicted mass and correct intensity is detected, the MS instrument can be directed to automatically obtain a product ion scan to further elucidate the structure. The Data files can then be used for multiple purposes: Fed into Meteor Nexus to filter the results tree (see figure 2) Fed into Meteor Nexus to allow structures to be assigned to detected metabolites Fed into metabolite ID software to improve report content Database report generated Mass defect is defined as the difference between the exact mass of a compound and its integer value. For example quetiapine has the following molecular properties: Molecular formula: C21H25N3O2S Exact mass: Nominal mass: 383 Mass defect: = One of the known active metabolites of quetiapine is 7 hydroxyquetiapine: Molecular formula: C21H25N3O3S Exact mass: Nominal mass: 399 Mass defect: = Subtracting the mass defect values of the metabolite and the parent gives the following result: = Using the Query Mass Defect filter in Meteor Nexus with the value (Tolerance = 1E-5) will only display metabolites where the molecular formula change is +O or has a mass increase of +16 e.g. hydroxylation, epoxidation or S or N oxidation. Mass defect filtering is not limited to Phase I oxidative biotransformations. It can also be applied to dehydration, nitro reduction and dealkylation reactions and Phase II metabolites such as glucuronidation ( ) or glutathione conjugation ( ). In summary, filtering by mass defect is a convenient way to reduce the number of metabolites that are displayed after a prediction has been made. Meteor Nexus can be used to help elucidate the likely chemical structures detected by a mass spectrometer and help predict likely metabolic pathways. Following processing of the parent compound through Meteor, a range of filters can be applied to provide a results tree that is consistent with the experimental findings (see figure 2). Meteor results can be used with a range of mass spec software, including those provided by the following vendors: Agilent Technologies Bruker Shimadzu ThermoFisher Scientific Waters Thermo Scientific Mass Frontier Spectral Interpretation Software LC/MS and GC/MS data is built into Spectral Trees within Mass Frontier software. The.mol files of the metabolites generated by Meteor can be imported into Mass Frontier, where their theoretical fragments can be generated and assigned to the corresponding MSn spectra. This facilitates the investigation of structure-spectra relationships which leads to confident structural identification. Figure 3 A workflow designed to improve efficiency and accuracy

5 Find out more about Meteor Nexus T: +44 (0) E: W: Connect with us on LinkedIn Who are we? Lhasa Limited is a not-for-profit organisation that facilitates collaborative data sharing projects in the pharmaceutical, cosmetics and chemistry-related industries. A pioneer in the production of knowledge based systems for forward thinking scientists, Lhasa Limited continues to draw on over thirty years of experience to create user-friendly, state of the art in silico prediction and database systems. What makes us special? We believe in Shared Knowledge Shared Progress. Our not-forprofit, member driven status is designed to facilitate collaborative working and confidential data sharing between organisations. We run collaborative projects with industry, academia and regulatory bodies to continually enhance all our products. What do we offer? Derek Nexus For predicting toxicity Derek Nexus is the expert, knowledge based software that gives you accurate toxicity predictions quickly. Early, accurate in silico toxicity tests using Derek Nexus is the quick, inexpensive way to identify potentially toxic chemicals, aiding your experts in rejecting unsuitable drug compounds. Sarah Nexus For predicting mutagenicity Lhasa offers a complete solution to meeting the ICH M7 guidelines by providing the expert system, Derek Nexus, and Sarah Nexus, a unique statistically based methodology. Access through a single interface allows easy input of structures for generation of independent predictions. Vitic Nexus For managing chemical information Zeneth For predicting forced degradation pathways Zeneth is the expert, knowledge based software that gives you accurate forced degradation predictions quickly. Zeneth is the perfect cost-effective solution for scientists who need to understand the forced degradation pathways of organic compounds. Other Activities Lhasa Limited is involved in various projects including: Playing a central role in etox by hosting and managing all the confidential data shared by the major pharmaceutical industries. Involvement in MIP-DILI, an EU project with the key aim of identifying a predictive screen to avoid liver injury. Lhasa Limited is also involved in and supporting cross-company learning through pre-competitive data sharing. These currently include excipients, intermediates, aromatic amines and aryl boronic acids. Vitic Nexus provides the largest non-confidential curated dataset of mutagens for Derek Nexus. Vitic Nexus is also used to facilitate data sharing initiatives between members, of which Boronic Acids, Vitic Intermediates, Vitic Excipients and Aromatic Amines are examples. shared knowledge shared progress Lhasa Limited Registered Office Granary Wharf House, 2 Canal Wharf, Leeds LS11 5PS Registered Charity (290866) +44 (0) info@lhasalimited.org Company Registration Number Registered in England and Wales. VAT Registration Number GB ISO 9001: CERTIFIED