Study of the dynamics of Ceritinib in complex with common variants of anaplastic lymphoma kinase

Almourfi, Feras; Singh, Inderpal; Shoket, Heena; Yadav, Arvind Kumar; Kandpal, Manoj

doi:10.1080/08927022.2020.1841186

Cited by 1 publication

(1 citation statement)

References 22 publications

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“…The dynamic cross-correlation matrix (DCCM) of all protein Ca atoms were calculated to reflect the inter-residue correlations [36][37][38][39][40]. The cross-correlation coefficient C ij was calculated by:…”

Section: Dynamic Cross-correlation Matrix (Dccm) Analysismentioning

confidence: 99%

Deciphering the resistance mechanism of RET kinase mutant against vandetanib and nintedanib using molecular dynamics simulations

Zheng

Liu

et al. 2021

Journal of Experimental Nanoscience

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The RET protein is a transmembrane receptor tyrosine kinase (RTK) whose oncogenic mutations or fusions are closely related to human cancers such as thyroid and non-small cell lung cancer. Vandetanib as a clinical-approved protein-tyrosine kinase inhibitor (TKI) exhibits anti-cancer efficacy by blocking the RET ATP-binding site, but drug resistance was observed for the RET G810A mutant. Recent studies have identified another TKI nintedanib as an effective molecule to inhibit vandetanib-resistant RET G810A . However, there is no clear evidence of why nintedanib and vandetanib displayed different inhibitory activities towards RET G810A . Here, we exploited molecular dynamic (MD) simulations to compare the interactions of the RET G810A mutant with nintedanib and vandetanib. A higher structural flexibility of the activation loop was observed in the nintedanib-bound RET G810A , which may result in discrepant autophosphorylation activity in the nintedanib-and vandetanib-bound RET kinase, causing differentiated pharmacological effects of the two compounds. Molecular mechanics/Poisson-Bolzmann surface area method suggested that nintedanib had a higher affinity towards RET G810A over vandetanib, accounting for its better inhibitory effect as an ATP-competitive compound. These results depicted the underlying mechanism for the different inhibitory efficacy of nintedanib and vandetanib on RET G810A from both conformational and energetic aspects. Furthermore, we also found that both compounds maintained the 'DFG-in, aC-helix-in, and activation loopopen' conformation of RET G810A , which is the characteristic of the active state. Together, our results provide comprehensive mechanistic insights into nintedanib's capability in inhibiting vandetanibresistant RET mutant and enlighten future structural-based optimisation of RET TKIs to overcome drug resistance.

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