Avirup Ghosh* and Hong Yan Pages 1 - 8 ( 8 )
Aims: To find out the potential reason behind the L858R and L858R/T790M non-small cell lung cancer occurrences specifically at the 858th and 790th positions in the EGFR.
Background: L858R mutation is one of the leading mutations for non-small cell lung cancer. It occurs in the kinase domain in the EGFR. After a median of ten months, another new mutation T790M occurs in the same kinase domain which creates drug resistance. Earlier research shows how the stability breaks down when the structures are changing from wild-type to L858R mutated structure and L858R mutated structure to L858R/T790M drug resistance structure.
Objective: In the current research work, we tried to predict, why the mutation occurs in those specific positions (858th and 790th) out of 270 possible positions in the kinase domain.
Method: We used the molecular dynamics simulation using Amber, for all three structures and after that, we analyzed the results using data analysis tool (R).
Result: From the obtained results, we found the count of hydrogen bonds at the 858th position and at the 790th position was significantly low for L858R mutated structure and L858R/T790M drug resistance structure respectively.
Conclusion: That demonstrates the stability failure at 858th and 790th position for both the structures. With the reducing count of hydrogen bonds, we can conclude the stability also reduces, so the energy increases of those two positions which support the mutational change to occur.
Other: The results achieved from this work will be helpful for advanced drug discovery.
EGFR, Non-small cell lung cancer (NSCLC), Gene mutation, Stability analysis
Department of Electrical Engineering, City University of Hong Kong, Kowloon, Department of Electrical Engineering, City University of Hong Kong, Kowloon