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Mutation-mediated influences on binding of anaplastic lymphoma kinase to crizotinib decoded by multiple replica
Jianzhong Chen1, Wei Wang2, Haibo Sun2
1School of Science, Shandong Jiaotong University, Jinan, 250357, China. chenjianzhong1970@163.com.
Abstract:
Anaplastic lymphoma kinase (ALK) has been thought to be a prospective target of anti-drug resistance design in treatment of tumors and specific neuron diseases. It is highly useful for the seeking of possible strategy alleviating drug resistance to probe the mutation-mediated effect on binding of inhibitors to ALK. In the current work, multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations, molecular mechanics generalized Born surface area (MM-GBSA) and free energy landscapes were coupled to explore influences of mutations L1198F, L1198F/C1156Y, and C1156Y on the binding of the first ALK inhibitor crizotinib to ALK. The results suggest that three mutations obviously affect structural flexibility, motion modes and conformational changes of ALKs. L1198F and L1198F/C1156Y strengthen the binding of crizotinib to the mutated ALKs but C1156Y induces evident drug resistance toward crizotinib. Analyses of free energy landscapes show that stability in the orientation and positions of crizotinib relative to ALK plays a vital role in alleviating drug resistance of mutations toward crizotinib. Residue-based free energy decomposition method was utilized to evaluate the contributions of separate residues to the binding of crizotinib. The results not only indicate that the tuning of point mutation L1198F on interaction networks of crizotinib with ALK can be regarded as a possible strategy to relieve drug resistance of the mutated ALK but also further verify that residues L1122, V1130, L1196, L1198, M1199, and L1256 can be used as efficient targets of anti-drug resistance design induced by mutations.
Insights
Anaplastic lymphoma kinase (ALK) mutations impact drug resistance. Specific mutations like L1198F can enhance inhibitor binding, while C1156Y causes resistance, offering targets for new drug designs.
Area of Science:
- Biochemistry and Molecular Biology
- Pharmacology
- Computational Biology
Background:
- Anaplastic lymphoma kinase (ALK) is a target for cancer and neurological disease therapies.
- Drug resistance is a major challenge in ALK-targeted treatments.
- Understanding mutation effects on inhibitor binding is crucial for overcoming resistance.
Purpose of the Study:
- To investigate how specific mutations (L1198F, L1198F/C1156Y, C1156Y) affect the binding of the ALK inhibitor crizotinib.
- To explore strategies for alleviating drug resistance in mutated ALK.
Main Methods:
- Multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations.
- Molecular mechanics generalized Born surface area (MM-GBSA) calculations.
- Free energy landscape analysis and residue-based free energy decomposition.
Main Results:
- Mutations L1198F and L1198F/C1156Y enhanced crizotinib binding to ALK.
- Mutation C1156Y induced significant drug resistance to crizotinib.
- Stable crizotinib orientation and position relative to ALK are key to overcoming resistance.
Conclusions:
- Tuning ALK mutations, like L1198F, can be a strategy to relieve drug resistance.
- Residues L1122, V1130, L1196, L1198, M1199, and L1256 are potential targets for anti-drug resistance design.
