期刊
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
卷 23, 期 34, 页码 18404-18413出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d1cp02783b
关键词
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资金
- National Natural Science Foundation of China (China) [82000074]
- Scientific Research Funding Project of Education Department of Liaoning Province (China) [jyt-dldxjc202005]
- Science and Technology Innovation Fund Project of Dalian (China) [2020JJ27SN071]
This study applied integrated molecular dynamics techniques to investigate the characteristics of 5-iTU and its derivatives targeting haspin, revealing the crucial role of 5-iTU in binding with haspin and the importance of gatekeeper Phe605.
As a human mitotic kinase, haspin is considered as a promising target for various diseases including cancers. However, no inhibitors targeting haspin have entered clinical trials presently. 5-iTU (5-iodotubercidin) is a useful and classical chemical probe for the investigation of haspin activity, but its inhibitory mechanism remains unclear. In this study, integrated molecular dynamics (MD) of conventional MD, extended adaptive biasing force (eABF), random acceleration MD and well-tempered metadynamics were applied to investigate the thermodynamic and kinetic features of 5-iTU and three derivatives targeting haspin. To emphasize the importance of gatekeeper Phe605, two haspin mutants (F605Y and F605T) were also built. The results showed that the binding affinity of 5-iTU and haspin was highest in all wild type (WT) systems, relying on the strong halogen aromatic pi interaction between 5-iTU and gatekeeper Phe605. Gatekeeper mutations, because of damage to this interaction, led to the rearrangement of water distributions at the binding site and the decrease of 5-iTU residence times. Additionally, compared with the smaller 5-fTU, 5-iTU dissociated from WT haspin with more difficulty through distinct unbinding pathways. These findings will provide crucial guidance for the design and development of novel haspin inhibitors and the rational modification of existing inhibitors.
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