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Mass Spectrometry: Alkyl Halide Fragmentation

Mass Spectrometry: Alkyl Halide Fragmentation

Chlorine isotopes exist as 35Cl and 37Cl in a 3:1 ratio, while bromine isotopes exist as 79Br and 81Br in a 1:1 ratio. The mass spectrum of alkyl halides typically produces two distinct molecular ion peaks, the molecular ion peak, [M], and the molecular ion plus two, [M + 2] peak. The relative heights of these two peaks are proportional to the isotopic abundance ratios of the halide. For example, 2‐chloropropane and 1‐bromopropane display two peaks with relative peak heights in a 3:1 and 1:1...

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Screening of a Halogen-Enriched Fragment Library Leads to Unconventional Binding Modes.

Marcel Dammann¹, Jason Stahlecker¹, Markus O Zimmermann¹

¹Laboratory for Molecular Design & Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, 72076Tübingen, Germany.

Journal of Medicinal Chemistry

|October 26, 2022

Summary

This study introduces a novel halogen-enriched fragment library (HEFLib) for drug discovery. It reveals that halogen bonds can enable unique binding modes in fragments, aiding early lead development.

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Area of Science:

Medicinal Chemistry
Structural Biology
Computational Chemistry

Background:

Halogen bonds are increasingly recognized for their role in molecular interactions.
Fragment-based drug discovery (FBDD) relies on small molecules to probe protein binding sites.
Exploring novel binding modes is crucial for identifying new drug leads.

Purpose of the Study:

To investigate the utility of halogen bonds in early-stage drug discovery using a dedicated fragment library.
To screen for fragments that bind to the human kinase DYRK1a.
To characterize the binding modes and affinities of identified fragments.

Main Methods:

Screening of the Halogen-Enriched Fragment Library (HEFLib) against DYRK1a.
Validation of fragment binding using isothermal titration calorimetry (ITC).
Determination of fragment-protein complex structure via X-ray crystallography.
Computational evaluation of halogen bond interactions using *ab initio* calculations.

Main Results:

Identification of micromolar binding fragments for DYRK1a.
Structural elucidation of a fragment revealing a noncanonical binding mode with a halogen bond.
Discovery of a secondary binding site occupied by the fragment, also featuring a halogen bond.
Structure-affinity relationship (SAR) studies indicated a promising fragment-growth vector.

Conclusions:

Halogen bonds can facilitate unique and exploitable binding modes in fragment-based drug discovery.
The HEFLib is a valuable tool for identifying novel interactions and leads.
Halogen bonding offers significant potential for early lead optimization and development.