Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 19, Issue 1, Pages -Publisher
MDPI
DOI: 10.3390/ijms19010111
Keywords
protein kinase CK2; allosteric inhibitor; fragment-based design; D region; linker
Funding
- National Natural Science Foundation of China [81402852]
- Beijing Natural Science Foundation [7152013]
- Beijing Municipal Commission of Education Research Projects [KM201610005031]
- China Scholarship Council [201706545010]
- Beijing Postdoctoral Science Foundation [2017-ZZ-015]
- Chaoyang District Postdoctoral Science Foundation [2017ZZ-01-26]
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Protein kinase is a novel therapeutic target for human diseases. The off-target and side effects of ATP-competitive inhibitors preclude them from the clinically relevant drugs. The compounds targeting the druggable allosteric sites outside the highly conversed ATP binding pocket have been identified as promising alternatives to overcome current barriers of ATP-competitive inhibitors. By simultaneously interacting with the D region (new allosteric site) and sub-ATP binding pocket, the attractive compound CAM4066 was named as allosteric inhibitor of CK2. It has been demonstrated that the rigid linker and non-ionizable substituted fragment resulted in significant decreased inhibitory activities of compounds. The molecular dynamics simulations and energy analysis revealed that the appropriate coupling between the linker and pharmacophore fragments were essential for binding of CAM4066 with CK2. The lower flexible linker of compound 21 lost the capability of coupling fragments A and B to D region and positive area, respectively, whereas the methyl benzoate of fragment B induced the re-orientated Pre-CAM4066 with the inappropriate polar interactions. Most importantly, the match between the optimized linker and pharmacophore fragments is the challenging work of fragment-linking based drug design. These results provide rational clues to further structural modification and development of highly potent allosteric inhibitors of CK2.
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