{"id":17259,"date":"2024-03-14T15:04:36","date_gmt":"2024-03-14T15:04:36","guid":{"rendered":"https:\/\/www.thermofisher.com\/blog\/analyteguru\/?p=17259"},"modified":"2024-05-07T16:08:27","modified_gmt":"2024-05-07T16:08:27","slug":"speed-up-drug-development-process","status":"publish","type":"post","link":"https:\/\/www.thermofisher.com\/blog\/analyteguru\/speed-up-drug-development-process\/","title":{"rendered":"Speed up Drug Development Process With Fit-for-Purpose Metabolite Identification Solutions"},"content":{"rendered":"\n

This is part one of a three-part series on Thermo Fisher Scientific\u2019s analytical instrument solutions for metabolite identification in the small molecule drug development process<\/em>.<\/p>\n\n\n\n

Metabolite identification (MetID) is a crucial and integral part of traditional small molecule drug discovery and development. In this context, metabolism describes the breakdown and conversion of xenobiotics into molecules that can be excreted from the body, as shown in Figure 1. However, rapid metabolism reduces the duration and potential efficacy of pharmaceuticals, so in early drug discovery stages, metabolic profiling from in vitro<\/em> studies is employed to identify metabolic soft spots to inform optimization of lead compounds to attain desired pharmacokinetics. Additionally, metabolic profiling plays a critical role in evaluating the safety of the molecule, as intermediates in the drug metabolism can have toxic effects. As a result, regulatory bodies have published detailed guidance on required testing. (See relevant  FDA guidance<\/a>). <\/p>\n\n\n\n

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As described in this application note<\/a> from Kate Comstock, et al.<\/em>, the Thermo Scientific Orbitrap Exploris 240<\/a> mass spectrometer can provide straightforward and comprehensive metabolite profiling, allowing informed decision-making for lead optimization efforts. This is enabled by sensitive high-resolution accurate mass measurements, fast polarity switching and MS2<\/sup> fragmentation capabilities of the Orbitrap Exploris 240 MS. This is complemented with the intelligent AcquireX data acquisition mode and advanced data processing in the Thermo Scientific Compound Discoverer<\/a> software.<\/p>\n\n\n\n

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Figure 1. Overview of drug metabolism for a xenobiotic compound with Phase I and II denoting different transformation reactions to 1) oxidize or introduce reactive groups and 2) conjugate polar species to increase hydrophilicity.<\/em><\/figcaption><\/figure>\n\n\n\n

The application note further describes the data processing workflow with the Compound Discoverer software that effectively mines the data to enable metabolite profiling and identification using predefined processing templates. The software relies on both a targeted approach to detect predicted metabolites generated based on intelligent dealkylation\/diarylation prediction and common metabolic pathways, as well as an orthogonal approach to identify unexpected or unknown metabolites based on isotopic pattern matching and compound class scoring.<\/p>\n\n\n\n