A novel and rapid encoding method based on mass spectrometry for "one-bead-one-compound" small molecule combinatorial...

Area of Science:

• Medicinal Chemistry
• Analytical Chemistry
• Biotechnology

Background:

• Combinatorial libraries are crucial for drug discovery.
• Efficient encoding and decoding methods are needed for large-scale synthesis.
• Mass spectrometry offers high sensitivity and specificity for molecular identification.

Purpose of the Study:

• To develop a novel and efficient encoding method for "one-bead-one-compound" small molecule combinatorial libraries.
• To integrate encoding with library synthesis and screening using mass spectrometry.
• To demonstrate the feasibility and accuracy of the developed method.

Main Methods:

• Preparation of topologically segregated bifunctional resin beads with orthogonal protecting groups.
• Derivatization of the bead's inner core with coding blocks on a cleavable linker.
• Concurrent synthesis of library compounds on the scaffold and coding blocks.
• Release and molecular mass determination of coding tags using matrix-assisted laser desorption ionization Fourier transform mass spectrometry (MALDI-FTMS).

Main Results:

• Successful synthesis and screening of a model small molecule library with 84,672 compounds.
• Identification of 17 streptavidin binding ligands with structural similarity.
• Clear and unambiguous decoding of chemical structures based on coding tag molecular masses.
• Demonstration of the method's efficiency and feasibility.

Conclusions:

• The developed mass spectrometry-based encoding method is efficient for "one-bead-one-compound" libraries.
• This approach allows for straightforward identification of synthesized small molecules.
• The method holds significant potential for accelerating drug discovery and chemical biology research.