Determining the binding mode and binding affinity constant of tyrosine kinase inhibitor PD153035 to DNA using optical tweezers.
Accurately predicting binding affinity constant (K(A)) is highly required to determine the binding energetics of the driving forces in drug-DNA interactions. Recently, PD153035, brominated anilinoquinazoline, has been reported to be not only a highly selective inhibitor of epidermal growth factor receptor but also a DNA intercalator. Here, we use a dual-trap optical tweezers to determining K(A) for PD153035, where K(A) is determined from the changes in B-form contour length (L) of PD153035-DNA complex. Here, L is fitted using a modified wormlike chain model. We found that a noticeable increment in L in 1 mM sodium cacodylate was exhibited. Furthermore, our results showed that K(A)=1.18(±0.09)×10(4) (1/M) at 23±0.5°C and the minimum distance between adjacent bound PD153035≈11 bp. We anticipate that by using this approach we can determine the complete thermodynamic profiles due to the presence of DNA intercalators.
School of Dental Technology, Taipei Medical University, Taipei 110, Taiwan.
Chih-Ming
CM
Cheng
Yuarn-Jang
YJ
Lee
Wei-Ting
WT
Wang
Chien-Ting
CT
Hsu
Jing-Shin
JS
Tsai
Chien-Ming
CM
Wu
Keng-Liang
KL
Ou
Tzu-Sen
TS
Yang
D000970:Antineoplastic Agents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry*; D052898:Optical Tweezers; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000737:chemistry*; D013816:Thermodynamics
D000970:Antineoplastic Agents; D007364:Intercalating Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D004247:DNA; D011505:Protein-Tyrosine Kinases; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline