Antiangiogenic Activity and in Silico Cereblon Binding Analysis of Novel Thalidomide Analogs

Due to its antiangiogenic and anti-immunomodulatory activity, thalidomide continues to be of clinical interest despite its teratogenic actions, and efforts to synthesize safer, clinically active thalidomide analogs are continually underway. In this study, a cohort of 27 chemically diverse thalidomid...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2020-12, Vol.25 (23), p.5683
Main Authors: Peach, Megan L, Beedie, Shaunna L, Chau, Cindy H, Collins, Matthew K, Markolovic, Suzana, Luo, Weiming, Tweedie, David, Steinebach, Christian, Greig, Nigel H, Gütschow, Michael, Vargesson, Neil, Nicklaus, Marc C, Figg, William D
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Analogs
Angiogenesis
Angiogenesis Inhibitors - chemistry
Angiogenesis Inhibitors - pharmacology
Animals
Antiangiogenics
Aorta
Aorta - drug effects
Binding
Binding sites
cereblon
Computer Simulation
Coronary vessels
Crystal structure
docking
Humans
Hydrogen bonds
Immunomodulation
Investigations
Kinases
Ligands
Male
Molecular docking
Molecular Docking Simulation
Molecular structure
Neovascularization, Physiologic - drug effects
Packaging
Proteins
Rats
Rats, Sprague-Dawley
structure–activity relationships
Teratogenicity
Thalidomide
Thalidomide - analogs & derivatives
Thalidomide - pharmacology
Ubiquitin-Protein Ligases - metabolism
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Summary:Due to its antiangiogenic and anti-immunomodulatory activity, thalidomide continues to be of clinical interest despite its teratogenic actions, and efforts to synthesize safer, clinically active thalidomide analogs are continually underway. In this study, a cohort of 27 chemically diverse thalidomide analogs was evaluated for antiangiogenic activity in an ex vivo rat aorta ring assay. The protein cereblon has been identified as the target for thalidomide, and in silico pharmacophore analysis and molecular docking with a crystal structure of human cereblon were used to investigate the cereblon binding abilities of the thalidomide analogs. The results suggest that not all antiangiogenic thalidomide analogs can bind cereblon, and multiple targets and mechanisms of action may be involved.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules25235683