Final ProgramCPSA 2011
Science and Technology Coming Together to Make a Difference
October 3 - 6, 2011
Bucks County Sheraton Hotel
Langhorne, PA
Program Abstract
Tuesday, Metabolite Identification Session
Evaluation of Mass-Metasite Software for Preliminary Metabolite Screening in Lead Optimization
Diane Grotz1, Thomas Bateman2, Qing Chen2, Mingxiang Lin1, Honglu Zhang1, Kevin Bateman3
1 Merck Research Labs, Dept. of Drug Metabolism and Pharmacokinetics, Kenilworth, NJ
2 Merck Research Labs, Dept. of Drug Metabolism and Pharmacokinetics, Rahway, NJ
3 Merck Research Labs, Dept. of Drug Metabolism and Pharmacokinetics, West Point, PA
Metabolite detection and structure elucidation is the crucial step of biotransformation studies in drug discovery and development process. Traditionally, this process has been conducted with unit resolution mass spectrometers followed by time consuming and labor intensive manual interpretation of mass spectra. In recent years, there has been a shift toward high resolution mass spectrometry (HRMS) based accurate mass measurements. The availability of elemental composition for a precursor ion and its fragment ions in spectra has greatly enhanced the confidence in software facilitated structure assignment, and metabolic transformation of drug candidates. Additionally, combining accurate mass measurements and the mass defect filter (MDF) have significantly reduced the false positive in metabolite identification and increase the throughput. However, until recently, MDF technique and neutral loss scan were mainly used for post-acquisition processing of data acquired using HRMS mass spectrometers. Recently introduced multiple mass defect triggered IDA (Information Dependent Acquisition) improved efficiency and reduces the need for multiple injections to get comprehensive metabolism information. In addition, neutral loss (NL) triggered IDA provides unique specificity by triggering MS/MS when two TOF-MS/MS scans (high and low energy) detect a specific accurate mass difference. Both positive and negative ionization modes were utilized to explore with NL scan to detect reactive metabolite. The result is more efficient IDA experiments with fewer runs and repeat injections. Metabolite PilotTM software automatically predicted some of the potential cleavage metabolites based on the parent compound structure, calculated MDF for phase I, II metabolites, parent compound, as well as potential cleavage metabolites. Metabolite PilotTM also allowed the application of multiple MDF, isotope pattern based metabolite search, and metabolite search based on common product ions or neutral loss simultaneously to streamline the overall metabolite identification workflow.
Return to program