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Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
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Targeting undruggable carbohydrate recognition sites through focused fragment library design
Elena Shanina1,2, Sakonwan Kuhaudomlarp3,4,5, Eike Siebs6,7,8
1Max Planck Institute of Colloids and Interfaces, Department of Biomolecular Systems, Am Mühlenberg 1, 14424, Potsdam, Germany.
Communications Chemistry
|January 25, 2023
Summary
Metal-binding pharmacophores (MBPs) offer a novel approach to inhibit calcium-dependent carbohydrate-protein interactions. This study identifies MBPs as effective inhibitors for key lectins, paving the way for new drug discovery strategies.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- Carbohydrate-protein interactions are crucial for cellular processes and host-pathogen recognition.
- The hydrophilic nature of these interactions presents challenges for developing effective inhibitors.
- Calcium (Ca2+)-dependent lectin interactions are significant therapeutic targets.
Purpose of the Study:
- To identify novel scaffolds for inhibiting Ca2+-dependent carbohydrate-protein interactions.
- To investigate the potential of metal-binding pharmacophores (MBPs) as inhibitors.
- To evaluate MBP efficacy against clinically relevant lectins.
Main Methods:
- Screening of four fragment libraries to identify MBPs.
- Biochemical and structural investigations of MBP-lectin interactions.
- Structure-activity relationship (SAR) studies of identified fragments.
- Assessment of inhibitor binding to DC-SIGN-expressing cells.
Main Results:
- MBPs were identified as effective inhibitors of Ca2+-dependent carbohydrate-protein interactions.
- Specificity of MBPs for different lectins (DC-SIGN, Langerin, LecA, LecB) was demonstrated.
- SAR studies revealed key functional groups for optimizing MBP inhibitors.
- Selected MBPs showed efficient binding to DC-SIGN-expressing cells.
Conclusions:
- MBPs represent a promising class of inhibitors for Ca2+-dependent lectins.
- This discovery provides a foundation for fragment-based ligand design.
- MBPs offer a viable strategy to overcome challenges in targeting hydrophilic interactions for drug development.
