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A computational study to reveal selpercatinib resistance to RET kinase double mutant V804M/Y806C

Guodong Zheng, Minyu Li, Jingfeng Zhang, Wuxia Liu, Lei Jiang, Wenqi Liang, Jialin Wang, Hong Shi, Zhoujun Kang, and Bin Zhou

Department of VIP Clinic, Changhai Hospital, Affiliated to Navy Medical University, Shanghai, China



Received: 19 June 2022  Accepted: 7 September 2022


As a member of the receptor tyrosine kinase family, rearranged during transfection (RET) kinase has received increased interest as a therapeutic target for the treatment of thyroid cancer and non-small cell lung cancer (NSCLC). Selpercatinib has recently been approved by the US FDA for the treatment of RET fusion-positive thyroid cancer and NSCLC. However, the RET double mutation V804M/Y806C confers resistance to selpercatinib. Here, multiple μs molecular dynamics (MD) simulations and binding free energy calculations were performed to reveal the mechanism of selpercatinib resistance to the RET double mutant V804M/Y806C. Our results show that the double mutation has a minor effect on the overall conformational dynamics of the RET kinase domain. Obviously, the binding free energies calculated by the MM/GBSA method based on the MD simulations reveal that the dominant energy contributions for selpercatinib binding derive from the van der Waals interactions. Moreover, the per-residue free energy decomposition analysis unveils that Tyr806 at the hinge region plays an important role in the binding of selpercatinib through hydrophobic interactions. This study will provide useful information for understanding the mechanism of selpercatinib resistance to the RET double mutant V804M/Y806C.

Keywords: Molecular dynamics simulations; Binding free energy calculations; RET; Selpercatinib; Receptor tyrosine kinase

Full paper is available at

DOI: 10.1007/s11696-022-02479-4


Chemical Papers 77 (1) 159–168 (2023)

Sunday, April 21, 2024

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