2019年
Encounter complexes and hidden poses of kinase-inhibitor binding on the free-energy landscape
Proceedings of the National Academy of Sciences
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- 巻
- 116
- 号
- 37
- 開始ページ
- 18404
- 終了ページ
- 18409
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1073/pnas.1904707116
- 出版者・発行元
- National Acad Sciences
<jats:p>Modern drug discovery increasingly focuses on the drug-target binding kinetics which depend on drug (un)binding pathways. The conventional molecular dynamics simulation can observe only a few binding events even using the fastest supercomputer. Here, we develop 2D gREST/REUS simulation with enhanced flexibility of the ligand and the protein binding site. Simulation (43 μs in total) applied to an inhibitor binding to c-Src kinase covers 100 binding and unbinding events. On the statistically converged free-energy landscapes, we succeed in predicting the X-ray binding structure, including water positions. Furthermore, we characterize hidden semibound poses and transient encounter complexes on the free-energy landscapes. Regulatory residues distant from the catalytic core are responsible for the initial inhibitor uptake and regulation of subsequent bindings, which was unresolved by experiments. Stabilizing/blocking of either the semibound poses or the encounter complexes can be an effective strategy to optimize drug-target residence time.</jats:p>
- リンク情報
- ID情報
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- DOI : 10.1073/pnas.1904707116
- ISSN : 1091-6490
- ISSN : 0027-8424
- ORCIDのPut Code : 92592168
- Web of Science ID : WOS:000485145400043