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Identifying EGFR mutation-induced drug resistance based on alpha shape model analysis of the dynamics

View Article: PubMed Central - PubMed

ABSTRACT

Background: Epidermal growth factor receptor (EGFR) mutation-induced drug resistance is a difficult problem in lung cancer treatment. Studying the molecular mechanisms of drug resistance can help to develop corresponding treatment strategies and benefit new drug design.

Methods: In this study, Rosetta was employed to model the EGFR mutant structures. Then Amber was carried out to conduct molecular dynamics (MD) simulation. Afterwards, we used Computational Geometry Algorithms Library (CGAL) to compute the alpha shape model of the mutants.

Results: We analyzed the EGFR mutation-induced drug resistance based on the motion trajectories obtained from MD simulation. We computed alpha shape model of all the trajectory frames for each mutation type. Solid angle was used to characterize the curvature of the atoms at the drug binding site. We measured the knob level of the drug binding pocket of each mutant from two ways and analyzed its relationship with the drug response level. Results show that 90 % of the mutants can be grouped correctly by setting a certain knob level threshold.

Conclusions: There is a strong correlation between the geometric properties of the drug binding pocket of the EGFR mutants and the corresponding drug responses, which can be used to predict the response of a new EGFR mutant to a drug molecule.

No MeSH data available.


Related in: MedlinePlus

a to d presents the comparison of the solid angle values of the atoms at the average binding site of the drug Response mutants delE746_T751insV (RL = 1, a and c) and delE746_A750 (RL = 2, b and d), and the No-response ones delL747_K754insANKG (RL = 4) and S768I_V774M (RL = 3). The drug Response and No-response mutants are shown in blue and red, respectively. e and f show the statistics of the convex atoms and the atoms with SA > 0.7 at the average binding site of the 30 mutants. The mutants of each response level group are sorted in an ascending order by the number of convex atoms. Blue, red, green and magenta correspond to mutants with RL = 1, 2, 3 and 4
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Fig5: a to d presents the comparison of the solid angle values of the atoms at the average binding site of the drug Response mutants delE746_T751insV (RL = 1, a and c) and delE746_A750 (RL = 2, b and d), and the No-response ones delL747_K754insANKG (RL = 4) and S768I_V774M (RL = 3). The drug Response and No-response mutants are shown in blue and red, respectively. e and f show the statistics of the convex atoms and the atoms with SA > 0.7 at the average binding site of the 30 mutants. The mutants of each response level group are sorted in an ascending order by the number of convex atoms. Blue, red, green and magenta correspond to mutants with RL = 1, 2, 3 and 4

Mentions: Besides the aforementioned definition of knob level, we alternatively computed the mean of the solid angle value of each atom at the drug binding site from the 200 trajectory frames. In this way, an average drug binding site of each mutant was obtained. Thus, we used the average convex degree of this drug binding site as the knob level to describe the mutant. Figures 5a to d show the comparison of the solid angle values of the atoms at the average binding site of the drug Response mutants delE746_T751insV (RL = 1) and delE746_A750 (RL = 2), and the No-response ones delL747_K754insANKG (RL = 4) and S768I_V774M (RL = 3). Although there is not much difference between the total number of convex atoms of the Response and No-response groups, the solid angle values of convex atoms in the No-response group are generally greater than that of the Response group. We also counted the number of convex atoms (SA > 0) and the number of atoms with SA > 0.7 at the average drug binding site of each mutant (Figs. 5e and f). The number of convex atoms of the 30 mutants is irregular for different response level groups. However, the number of atoms with SA > 0.7 of the No-response group is equal to or more than that of the Response group.Fig. 5


Identifying EGFR mutation-induced drug resistance based on alpha shape model analysis of the dynamics
a to d presents the comparison of the solid angle values of the atoms at the average binding site of the drug Response mutants delE746_T751insV (RL = 1, a and c) and delE746_A750 (RL = 2, b and d), and the No-response ones delL747_K754insANKG (RL = 4) and S768I_V774M (RL = 3). The drug Response and No-response mutants are shown in blue and red, respectively. e and f show the statistics of the convex atoms and the atoms with SA > 0.7 at the average binding site of the 30 mutants. The mutants of each response level group are sorted in an ascending order by the number of convex atoms. Blue, red, green and magenta correspond to mutants with RL = 1, 2, 3 and 4
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5015241&req=5

Fig5: a to d presents the comparison of the solid angle values of the atoms at the average binding site of the drug Response mutants delE746_T751insV (RL = 1, a and c) and delE746_A750 (RL = 2, b and d), and the No-response ones delL747_K754insANKG (RL = 4) and S768I_V774M (RL = 3). The drug Response and No-response mutants are shown in blue and red, respectively. e and f show the statistics of the convex atoms and the atoms with SA > 0.7 at the average binding site of the 30 mutants. The mutants of each response level group are sorted in an ascending order by the number of convex atoms. Blue, red, green and magenta correspond to mutants with RL = 1, 2, 3 and 4
Mentions: Besides the aforementioned definition of knob level, we alternatively computed the mean of the solid angle value of each atom at the drug binding site from the 200 trajectory frames. In this way, an average drug binding site of each mutant was obtained. Thus, we used the average convex degree of this drug binding site as the knob level to describe the mutant. Figures 5a to d show the comparison of the solid angle values of the atoms at the average binding site of the drug Response mutants delE746_T751insV (RL = 1) and delE746_A750 (RL = 2), and the No-response ones delL747_K754insANKG (RL = 4) and S768I_V774M (RL = 3). Although there is not much difference between the total number of convex atoms of the Response and No-response groups, the solid angle values of convex atoms in the No-response group are generally greater than that of the Response group. We also counted the number of convex atoms (SA > 0) and the number of atoms with SA > 0.7 at the average drug binding site of each mutant (Figs. 5e and f). The number of convex atoms of the 30 mutants is irregular for different response level groups. However, the number of atoms with SA > 0.7 of the No-response group is equal to or more than that of the Response group.Fig. 5

View Article: PubMed Central - PubMed

ABSTRACT

Background: Epidermal growth factor receptor (EGFR) mutation-induced drug resistance is a difficult problem in lung cancer treatment. Studying the molecular mechanisms of drug resistance can help to develop corresponding treatment strategies and benefit new drug design.

Methods: In this study, Rosetta was employed to model the EGFR mutant structures. Then Amber was carried out to conduct molecular dynamics (MD) simulation. Afterwards, we used Computational Geometry Algorithms Library (CGAL) to compute the alpha shape model of the mutants.

Results: We analyzed the EGFR mutation-induced drug resistance based on the motion trajectories obtained from MD simulation. We computed alpha shape model of all the trajectory frames for each mutation type. Solid angle was used to characterize the curvature of the atoms at the drug binding site. We measured the knob level of the drug binding pocket of each mutant from two ways and analyzed its relationship with the drug response level. Results show that 90 % of the mutants can be grouped correctly by setting a certain knob level threshold.

Conclusions: There is a strong correlation between the geometric properties of the drug binding pocket of the EGFR mutants and the corresponding drug responses, which can be used to predict the response of a new EGFR mutant to a drug molecule.

No MeSH data available.


Related in: MedlinePlus