Multivalent butyrylcholinesterase inhibitor discovered by exploiting dynamic combinatorial chemistry

Area of Science:

• Polymer Chemistry
• Medicinal Chemistry
• Enzyme Inhibition

Background:

• Cholinesterase enzymes, particularly butyrylcholinesterase (BChE) and acetylcholinesterase (AChE), are key targets in neurological disorders.
• Developing selective inhibitors for BChE is crucial for therapeutic applications, minimizing off-target effects.

Purpose of the Study:

• To synthesize a polymer-based dynamic combinatorial library (DCL) with exchangeable side chains.
• To identify potent BChE binding side chains using the DCL approach.
• To develop and evaluate a novel multivalent BChE inhibitor based on identified binding motifs.

Main Methods:

• Generation of a polymer-based DCL utilizing acylhydrazone formation for exchangeable side chains.
• Screening of the DCL in combination with tetrameric BChE to identify potent binding moieties.
• Synthesis of a multivalent inhibitor incorporating the identified BChE-specific side chains.
• In vitro evaluation of the multivalent inhibitor's efficacy and selectivity against BChE and AChE.

Main Results:

• Successful generation of a polymer-based DCL with tunable side chains.
• Identification of the most potent BChE binding side chain through library screening.
• Synthesis of a novel multivalent BChE inhibitor.
• The synthesized inhibitor demonstrated a superior inhibitory effect compared to a commercial reference.
• High selectivity was observed for BChE inhibition over AChE.

Conclusions:

• Polymer-based DCLs are effective tools for identifying potent enzyme inhibitors.
• The developed multivalent inhibitor represents a promising therapeutic candidate for BChE-related conditions.
• The study highlights the potential for selective BChE inhibition in drug discovery.