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Updated: Jul 15, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Insights into pralsetinib resistance to the non-gatekeeper RET kinase G810C mutation through molecular dynamics
Shu Cao1, Changbin Tan1, Anhua Fei1
1Department of Urology, Ezhou Central Hospital, Hubei, 436000, China.
Objective:
RET (rearranged during transfection) kinase, as a transmembrane receptor tyrosine kinase, is a therapeutic target for several human cancer such as non-small cell lung cancer (NSCLC) and thyroid cancer. Pralsetinib is a recently approved drug for the treatment of RET-driven NSCLC and thyroid cancers. A single point mutation G810C at the C-lobe of the RET kinase causes pralsetinib resistance to this non-gatekeeper variant. However, the detailed mechanism remains poorly understood.
Methods:
Here, multiple microsecond molecular dynamics (MD) simulations, molecular mechanics/generalized born surface area (MM/GBSA) binding free energy calculations, and community network analysis were performed to reveal the mechanism of pralsetinib resistance to the RET G810C mutant.
Results:
The simulations showed that the G810C mutation had a minor effect on the overall conformational dynamics of the RET kinase domain. Energetic analysis suggested that the G810C mutation reduced the binding affinity of pralsetinib to the mutant. Per-residue energy contribution and structural analyses revealed that the hydrogen bonding interactions between pralsetinib and the hinge residues Glu805 and Ala807 were disrupted in the G810C mutant, which were responsible for the decreased binding affinity of pralsetinib to the mutant.
Conclusions:
The obtained results may provide understanding of the mechanism of pralsetinib resistance to the non-gatekeeper RET G810C mutant.
Insights
The RET G810C mutation causes pralsetinib resistance by disrupting key hydrogen bonds in the RET kinase domain, reducing drug binding affinity. This finding explains resistance mechanisms in RET-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- RET (rearranged during transfection) kinase is a validated therapeutic target for cancers like non-small cell lung cancer (NSCLC) and thyroid cancer.
- Pralsetinib is an approved drug for treating RET-driven NSCLC and thyroid cancers.
- A G810C mutation in the RET kinase C-lobe confers resistance to pralsetinib, but the underlying mechanism is unclear.
Purpose of the Study:
- To elucidate the molecular mechanism by which the G810C mutation in RET kinase leads to pralsetinib resistance.
- To investigate the impact of the G810C mutation on pralsetinib binding affinity and the structural basis of resistance.
Main Methods:
- Utilized microsecond molecular dynamics (MD) simulations.
- Employed molecular mechanics/generalized Born surface area (MM/GBSA) for binding free energy calculations.
- Performed community network analysis to understand resistance mechanisms.
Main Results:
- The G810C mutation minimally affected overall RET kinase domain dynamics.
- Binding free energy calculations indicated reduced pralsetinib binding affinity to the G810C mutant.
- Disruption of hydrogen bonds between pralsetinib and hinge residues (Glu805, Ala807) was identified as the cause of decreased binding.
Conclusions:
- The study provides a detailed molecular understanding of pralsetinib resistance mediated by the non-gatekeeper RET G810C mutation.
- The findings highlight the importance of specific hydrogen bonding interactions for drug efficacy and offer insights for future drug development.
