Determining the binding mode and binding affinity constant of tyrosine kinase inhibitor PD153035 to DNA using optical tweezers |
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| Authors: | Cheng Chih-Ming Lee Yuarn-Jang Wang Wei-Ting Hsu Chien-Ting Tsai Jing-Shin Wu Chien-Ming Ou Keng-Liang Yang Tzu-Sen |
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| Institution: | aSchool of Dental Technology, Taipei Medical University, Taipei 110, Taiwan;bInstitute of Biomedical Materials and Engineering, Taipei Medical University, Taipei 110, Taiwan;cResearch Center for Biomedical Implants and Microsurgery Devices, Taipei Medical University, Taipei 110, Taiwan;dSection of Infectious Diseases, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan;eDepartment of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30043, Taiwan |
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| Abstract: | Accurately predicting binding affinity constant (KA) 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 KA for PD153035, where KA 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 KA = 1.18(±0.09) × 104 (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. |
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| Keywords: | PD153035 Non-small cell lung cancer Tyrosine kinase inhibitor Binding affinity constant Optical tweezers Wormlike chain model |
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