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Fragment-Based Dynamic Combinatorial Chemistry for Identification of Selective α-Glucosidase Inhibitors
Yao Wu1, Changming Liu1, Lei Hu1
1School of Pharmacy, Jiangsu University, 301 Xuefu Road, 212013 Zhenjiang, China.
ACS Medicinal Chemistry Letters
|November 17, 2022
Summary
This study combined fragment-based drug design and dynamic combinatorial chemistry to create selective alpha-glucosidase inhibitors. The best compound effectively inhibited alpha-glucosidase with high selectivity and low toxicity.
Area of Science:
- Medicinal Chemistry
- Enzyme Inhibition
- Drug Discovery
Background:
- Fragment-based drug design (FBDD) and dynamic combinatorial chemistry (DCC) are powerful approaches for identifying novel drug candidates.
- Selective inhibition of alpha-glucosidase is a key therapeutic strategy for managing type 2 diabetes.
- Combining FBDD and DCC offers a synergistic approach to accelerate the discovery of potent enzyme inhibitors.
Purpose of the Study:
- To develop selective alpha-glucosidase inhibitors by integrating FBDD and DCC methodologies.
- To generate and screen dynamic combinatorial libraries (DCLs) against alpha-glucosidase and alpha-amylase.
- To characterize the inhibition mechanism and binding interactions of the most promising inhibitor.
Main Methods:
- Rational design of 5 initial fragments for library synthesis.
- Iterative generation of two dynamic combinatorial libraries (DCLs) containing 29 acylhydrazone products.
- Screening of DCLs against alpha-glucosidase and alpha-amylase enzymes.
- Binding kinetic studies and molecular docking simulations for mechanistic elucidation.
Main Results:
- Successful generation and screening of 29 acylhydrazone compounds using a combined FBDD/DCC strategy.
- Identification of an optimal ligand exhibiting significant alpha-glucosidase inhibition.
- Demonstrated high selectivity of the inhibitor for alpha-glucosidase over alpha-amylase.
- Confirmed low cytotoxicity of the identified lead compound.
- Elucidation of the inhibition type and detailed binding interactions through kinetic and docking analyses.
Conclusions:
- The integrated FBDD and DCC approach is effective for discovering selective enzyme inhibitors.
- The identified acylhydrazone derivative represents a promising lead compound for alpha-glucosidase-targeted therapies.
- Detailed mechanistic insights were gained into ligand-enzyme interactions, guiding future drug optimization.
