Design and Synthesis of Small Molecule Probes of MDA-9/Syntenin

MDA-9/Syntenin, a key scaffolding protein and a molecular hub involved in a diverse range of cell signaling responses, has proved to be a challenging target for the design and discovery of small molecule probes. In this paper, we report on the design and synthesis of small molecule ligands of this k...

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Bibliographic Details
Published in:Biomolecules (Basel, Switzerland) Switzerland), 2024-10, Vol.14 (10), p.1287
Main Authors: Sankaranarayanan, Nehru Viji, Villuri, Bharath Kumar, Nagarajan, Balaji, Lewicki, Sarah, Das, Swadesh K, Fisher, Paul B, Desai, Umesh R
Format: Article
Language:English
Subjects:
Algorithms
anti-cancer agents
Binding sites
Cell signaling
Design
Design and construction
Drug Design
Genetic algorithms
Heparan sulfate
Humans
Ligands
Melanoma
Metastasis
molecular modeling
Molecular probes
Molecular Probes - chemical synthesis
Molecular Probes - chemistry
PDZ domain
Peptides
Physiological aspects
Probes
Protein biosynthesis
Protein folding
Proteins
protein–protein interactions
small molecule inhibitors
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - chemistry
Structure
Syntenins - chemistry
Syntenins - genetics
Syntenins - metabolism
Testing
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Summary:MDA-9/Syntenin, a key scaffolding protein and a molecular hub involved in a diverse range of cell signaling responses, has proved to be a challenging target for the design and discovery of small molecule probes. In this paper, we report on the design and synthesis of small molecule ligands of this key protein. Genetic algorithm-based computational design and the five-eight step synthesis of three molecules led to ligands with affinities in the range of 1-3 µM, a 20-60-fold improvement over literature reports. The design and synthesis strategies, coupled with the structure-dependent gain or loss in affinity, afford the deduction of principles that should guide the design of advanced probes of MDA-9/Syntenin.
ISSN:2218-273X
2218-273X
DOI:10.3390/biom14101287