Software Automation Tools for Increased Throughput Metabolic Soft-Spot Identification in Early Drug Discovery

Abstract

Review of these applications has demonstrated their utility in providing accurate results in a time-efficient manner, leading to acceleration of metabolite identification initiatives while highlighting the continued need for biotransformation expertise in the interpretation of more complex metabolic reactions.

Software‐aided cytochrome P450 reaction phenotyping and kinetic analysis in early drug discovery

“…The MS/MS fragment ions of the parent compound were compared with the MS/MS fragment ions of the metabolite. The conserved and shifted mass fragments identified by the spectral/structural comparison were used to calculate a score for each potential structural solution . In this way, structural elucidation was accomplished.…”

“…Metabolite identification (Met ID) is a key step that is necessary for understanding the metabolic properties of new chemical entities with respect to intrinsic clearance and metabolic pathways. Met ID is typically conducted during the drug discovery process, and Met ID studies play an important role in determining structure‐metabolism relationships (SMR), understanding metabolic stability, identifying chemically reactive metabolites and revealing 'metabolic soft spots' . The identification of the chemical structure of a metabolite helps medicinal chemists to design structural modifications of a lead compound to improve its metabolic clearance and to avoid the formation of potentially hepatotoxic metabolite species .…”

“…These data usually require a long time to analyze and involve some manual work in the interpretation of the results. The program MassMetaSite was developed to automate the analysis of HRMS data. The objective of the software was to enable computer‐assisted peak detection and tandem mass spectrometry (MS/MS) analysis.…”

Software‐aided structural elucidation in drug discovery

“…The established workflow for metabolite identification used in our laboratory was compared to a second workflow (Fig. , Workflow II) using a software tool built for computer‐assisted metabolite identification (Mass‐MetaSite) …”

“…1, Workflow II) using a software tool built for computer-assisted metabolite identification (Mass-MetaSite). [7][8][9][10][11] Mass-MetaSite is designed to facilitate the MetID process by aiding in the detection of chromatographic peaks associated with parent drug and potential metabolites and on the basis of MS fragmentation data to automatically suggest preliminary metabolite structures for further interrogation. The use of Mass-MetaSite for identification of phase I metabolites from microsomal incubations has been reported previously.…”