Software aided approaches to structure-based metabolite identification in drug discovery and development.

Technological advances in mass spectrometry (MS) such as accurate mass high resolution instrumentation have fundamentally changed the approach to systematic metabolite identification over the past decade. Despite technological break-through on the instrumental side, metabolite identification still requires tedious manual data inspection and interpretation of huge analytical datasets. The process of metabolite identification has become largely facilitated and partly automated by cheminformatics approaches such as knowledge base metabolite prediction using, for example, Meteor, MetaDrug, MetaSite and StarDrop that are typically applied pre-acquisition. Likewise, emerging new technologies in postacquisition data analysis like mass defect filtering (MDF) have moved the technology driven analytical methodology to metabolite identification toward generic, structure-based workflows. The biggest challenge for automation however remains the structural assignment of drug metabolites. Software-guided approaches for the unsupervised metabolite identification still cannot compete with expert user manual data interpretation yet. Recently MassMetaSite has been introduced for the automated ranked output of metabolite structures based on the combination of metabolite prediction and interrogation of analytical mass spectrometric data. This approach and others are promising milestones toward an unsupervised process to metabolite identification and structural characterization moving away from a sample focused per-compound approach to a structure-driven generic workflow.