Data Independent HDMSE High Throughput Drug Library Screening Using the DESI XS Source

Význam tématu

Rapid, high-throughput screening of small molecule libraries is critical in pharmaceutical development and quality control. Traditional LC-MS methods provide reliable identification but can be time-consuming. Combining desorption electrospray ionization (DESI) with ion mobility–enabled high-resolution mass spectrometry (IMS-HRMS) offers a direct, surface-based approach that drastically reduces analysis time while retaining rich structural information.

Cíle a přehled studie / článku

This study evaluates the performance of the DESI XS source coupled to a Waters SYNAPT XS mass spectrometer operating in positive HDMSE mode for screening 96 FDA-approved small molecule drugs. Key objectives include assessing detection rates, comparing collision cross section (CCS) data to an LC-generated library, and demonstrating throughput capabilities.

Použitá metodika a instrumentace

Sample Preparation:

• Standards prepared at ~100–250 µg/mL in methanol or water:methanol.
• 3 µL of each drug spotted onto Teflon-coated glass slides, dried under vacuum.

Instrumentation and Conditions:

• Source: DESI XS with high-performance sprayer.
• Mass Spectrometer: SYNAPT XS operating in positive HDMSE (low/high energy channels with IMS).
• Solvent: 98:2 methanol:water with 0.1% formic acid.
• Capillary voltage 1.1 kV, cone voltage 60 V, gas flow 15 psi, source temp 150 °C.
• Scan speed 10 Hz, pixel size 500 µm, m/z range 100–1200.
• Software: MassLynx v4.2, HDI v1.6, UNIFI v1.9.2.

Hlavní výsledky a diskuse

Throughput and Detection:

• Analysis of 11 samples in ~20 s (~2 s per sample), yielding <3 s cycle time for large arrays.
• Automatic identification of 76% of compounds; manual review increased coverage to 84% (81/96 drugs).
• LC-MS comparison identified 88% of the same standards.

Spectral Quality and CCS Correlation:

• DESI produces clean spectra with minimal in-source fragmentation; high-energy fragmentation remains available for structural confirmation.
• Analytically derived CCS values from DESI strongly correlate (R²>0.997) with LC-MS CCS data, supporting cross-platform library use.

Přínosy a praktické využití metody

• Greatly increased sample throughput for library screening and synthetic confirmation.
• Minimal sample preparation and no autosampler required, enabling near-continuous operation.
• Capability to build and match against CCS-enriched libraries for confident compound identification.
• Potential for automation and integration into QA/QC workflows.

Budoucí trendy a možnosti využití

• Expanding DESI-IMS applications to complex mixtures and tissue imaging.
• Integration with automated slide handling systems for fully unattended screening.
• Advances in ion mobility resolution and data processing algorithms for deeper structural insights.
• Use of AI-driven library matching and anomaly detection in high-throughput settings.

Závěr

The DESI XS source coupled to a SYNAPT XS mass spectrometer demonstrates a powerful workflow for rapid, high-throughput drug library screening. It achieves near-LC performance in compound detection and CCS matching while offering dramatic time savings and minimal sample handling. This approach is well suited for pharmaceutical screening, medicinal chemistry, and quality control applications.

Reference

1. Waters Corporation. A Combination of High Sensitivity and High Mass Resolution Imaging at Speed, With DESI XS on the SYNAPT XS HDMS. Waters Brochure 720007236EN.
2. Morato NM, Cooks RG. Inter-Platform Assessment of Performance of High-Throughput Desorption Electrospray Ionization Mass Spectrometry. Talanta Open. 2021;4:100046.