The Effect of Conformational Flexibility on Binding Free Energy Estimation between Kinases and Their Inhibitors
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- 作者：Mitsugu Araki ; Narutoshi Kamiya ; Miwa Sato ; Masahiko Nakatsui ; Takatsugu Hirokawa ; Yasushi Okuno
- 刊名：Journal of Chemical Information and Modeling
- 出版年：2016
- 出版时间：December 27, 2016
- 年：2016
- 卷：56
- 期：12
- 页码：2445-2456
- 全文大小：892K
- ISSN：1549-960X
文摘
Accurate prediction of binding affinities of drug candidates to their targets remains challenging because of protein flexibility in solution. Conformational flexibility of the ATP-binding site in the CDK2 and ERK2 kinases was identified using molecular dynamics simulations. The binding free energy (ΔG) of twenty-four ATP-competitive inhibitors toward these kinases was assessed using an alchemical free energy perturbation method, MP-CAFEE. However, large calculation errors of 2–3 kcal/mol were observed using this method, where the free energy simulation starts from a single equilibrated conformation. Here, we developed a new ΔG computation method, where the starting structure was set to multiconformations to cover flexibility. The calculation accuracy was successfully improved, especially for larger molecular size compounds, leading to reliable prediction of a broader range of drug candidates. The present study demonstrates that conformational flexibility of interactions between a compound and the glycine-rich loop in the kinases is a key factor in ΔG estimation.