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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.


The relationship between the knob level of the average binding site and the drug response level of the mutants, with the solid angle value threshold setting to 0, 0.01 and 0.02 respectively
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Fig6: The relationship between the knob level of the average binding site and the drug response level of the mutants, with the solid angle value threshold setting to 0, 0.01 and 0.02 respectively

Mentions: Afterwards, we used the average convex degree (the sum of all the solid angle values of convex atoms at the average drug binding site divided by the total number of convex atoms in this area) to characterize the knob level of the average drug binding site of each mutant. Similarly, some solid angle values are close to zero, and we set a solid angle value threshold to remove their influence. The relationship between knob level and drug response level of the mutants are shown in Fig. 6. When the solid angle value threshold equals to 0.01 or 0.02, only three mutants of the two groups (Response and No-response groups) are wrongly distinguished by setting a certain knob level boundary (dark dashed lines in Figs. 6b and c), showing an accuracy of 90 % (27/30). In addition, the main bodies of the two groups of mutants are in different knob level ranges.Fig. 6


Identifying EGFR mutation-induced drug resistance based on alpha shape model analysis of the dynamics
The relationship between the knob level of the average binding site and the drug response level of the mutants, with the solid angle value threshold setting to 0, 0.01 and 0.02 respectively
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig6: The relationship between the knob level of the average binding site and the drug response level of the mutants, with the solid angle value threshold setting to 0, 0.01 and 0.02 respectively
Mentions: Afterwards, we used the average convex degree (the sum of all the solid angle values of convex atoms at the average drug binding site divided by the total number of convex atoms in this area) to characterize the knob level of the average drug binding site of each mutant. Similarly, some solid angle values are close to zero, and we set a solid angle value threshold to remove their influence. The relationship between knob level and drug response level of the mutants are shown in Fig. 6. When the solid angle value threshold equals to 0.01 or 0.02, only three mutants of the two groups (Response and No-response groups) are wrongly distinguished by setting a certain knob level boundary (dark dashed lines in Figs. 6b and c), showing an accuracy of 90 % (27/30). In addition, the main bodies of the two groups of mutants are in different knob level ranges.Fig. 6

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.