Chemical Space Coverage in Liquid Chromatography

Chemical Space Coverage in Liquid Chromatography

Investigating chemical space coverage of liquid chromatographic techniques (Literature Thesis - MSc Chemistry)

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Analytical Sciences: Literature Thesis

Investigating the Chemical Space Coverage of Liquid Chromatographic Techniques: How Selectivity Drives Measurability

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• Introduction and NTA Context: Introduction to exposome and analytical challenges.
• Methodology: Methodological approach using RepoRT repository.
• Analysis of Chemical Coverage: Analysis of LC setups and chemical space coverage.
• Conclusions and Future Outlook: Summary of findings and perspectives.

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• Introduction to Exposome and Chemical Space
• The Selectivity-Measurability Bias
• Methodology: RepoRT Repository Analysis
• Key Findings and Chemical Coverage Trends
• Conclusions and Perspectives

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1

Introduction and Methodology

Understanding Exposome analysis through RepoRT repository

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• The exposome covers all chemical and non-chemical exposures throughout a lifetime.
• Non-targeted analysis (NTA) with LC-HRMS is essential for identifying thousands of unknown compounds.
• Comprehensive measurability is limited by analytical methods (sample prep, separation, detection).
• "Selectivity-measurability bias": only compounds interacting with the chosen system are retained and detected.

• Exposome includes all lifetime chemical and non-chemical exposures related to health.
• Non-targeted analysis (NTA) combined with LC-HRMS is crucial for identifying unknown compounds.
• Selectivity-measurability bias: Only analytes interacting with LC phases are effectively measured.
• RepoRT repository: Used for data-driven assessment of 236 curated LC methods.

• Dataset: 236 curated LC methods from the RepoRT repository.
• Focus: 75,797 reported compounds across 8 USP-classified column types.
• Data Processing: Julia programming language used to handle setup metadata and chemical descriptors.
• Chemical Descriptors: Exact mass, predicted log-P, TPSA, H-bond donors/acceptors retrieved from PubChem.

2

Key Findings and Analysis

Evaluating chemical space coverage of current LC methods

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• 236: LC Methods
• 75,797: Total Compounds
• 17,083: Unique Structures
• 89%: RPLC Dominance

• 17,083: Unique Compounds
• 89%: RPLC Dominance
• 11%: HILIC Representation
• ~31%: PCA Explained Variance

Chemical Space Coverage Reported compounds span broad theoretical regions: TPSA 0-852 Ų and log-P -11.0-26.6. However, the effectively covered region is much narrower (TPSA 0-200 Ų, log-P -4 to 9).

Selectivity Impact Methods are dominated by RPLC (89%), biasing measurability towards mid-polar and hydrophobic compounds. HILIC (11%) is currently underutilized, limiting the detection of highly polar analytes.

Theoretical vs. Actual Coverage Theoretical chemical space for compounds < 500 Da is huge (10^60 structures). The reported data covers 0-852 Ų (TPSA) and -11 to 26.6 (log-P).

The "Adequate" Region Most measurements are restricted to a much narrower range: TPSA 0-200 Ų (>94% of compounds) and log-P -4 to 9 (>95% of compounds).

Current LC workflows are effective but insufficient for complete chemical space characterization; orthogonal techniques are essential.

Future perspectives for exposome research

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Current LC methods are substantial but limited; complete coverage of chemical space remains unachievable with current chromatographic strategies alone.

Addressing future analytical needs in exposome research.

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• Future NTA research must prioritize exclusively NTA-generated datasets.
• Need to increase chromatographic diversity by incorporating GC, SFC, and IC.
• Future studies should include detailed variables like eluent pH and gradient profiles for better insights.
• Complete chemical coverage is far from realistic under current conditions, necessitating multimodal analytical strategies.