Analysis of the Relative Movements Between EGFR and Drug Inhibitors Based on Molecular Dynamics Simulation

Background: Mutation of EGFR is one of the most important drivers of non-small cell lung cancer. Many selective therapies take specific mutation of EGFR as target. For example, gefitinib is a commonly used front line drug for the mutations of exon 19 deletions and the L858R. New irreversible inhibitors, such as WZ4002, CO-1686, and AZD9291, are developed to overcome drug resistance caused by the acquired T790M mutation. Objective: In this study, a novel method is proposed to calculate the movement intensities of drug inhibitors relative to EGFR based on molecular dynamics (MD) simulation, in order to find the relationship of movements and drug resistances of gefitinib, WZ4002, CO-1686, and AZD9291. Method: The 4*33 complexes of four inhibitors (gefitinib, WZ4002, CO-1686 and AZD9291) with 32 common EGFR mutations as well as the wild type are analyzed. First, each EGFR-inhibitor complex is fixed to the EGFR backbone. Then each inhibitor is seen as a rigid body. Two kinds of relative movement intensities between EGFR and drug inhibitor are obtained by calculating the attitude parameter of the rigid body. Results: First, for most cases, irreversible inhibitors (WZ4002, CO-1686 and AZD9291) were observed to be more stable than reversible gefitinib, proving our method to be effective. Second, high correlation was obtained between clinical effects and the relative movement intensities. Especially for patients' response level, the correlation P-value was observed to be 0.0462 in the best case. Conclusion: Our method represents an important contribution to molecular dynamics analysis of drug inhibitors. The analysis results of WZ4002, CO-1686 and AZD9291 are useful for drug selection for patients with specific EGFR mutation.