Novel poly(ADP-ribose) polymerase inhibitor veliparib: biophysical studies on its binding to calf thymus DNA

作者：Yang, Hongqin; Tang, Peixiao; Tang, Bin; Huang, Yanmei; Xiong, Xinnuo; Li, Hui^*

来源：RSC Advances, 2017, 7(17): 10242-10251.

DOI：10.1039/c6ra28213j

• HUMAN SERUM-ALBUMIN
• SPECTROSCOPIC APPROACH
• IMIDAZOLE DERIVATIVES
• PARP INHIBITORS
• ABT-888
• MECHANISM
• BROMIDE

Veliparib (ABT-888), which can inhibit cancer growth by blocking DNA base excision repair, is one of several recently developed oral inhibitors of poly(ADP-ribose) polymerases, which are currently used in clinical trials. In this work, interaction of calf thymus DNA (ctDNA) with ABT-888 was first investigated following UV-visible absorption, nuclear magnetic resonance (NMR) spectroscopy, steady-state and time-resolved fluorescence, viscosity measurements, circular dichroism (CD), and Fourier transform infrared (FT-IR) spectroscopy coupled with molecular docking methods. UV-visible absorption indicated that ABT-888 was indeed bound to ctDNA. Broadening and upfield shift of the proton peaks of ABT-888 in the proton NMR spectrum indicated that ABT-888 interacted with ctDNA primarily by partial intercalation. Fluorescence quenching and time-resolved fluorescence spectroscopy studies showed that binding of ABT-888 with ctDNA occurred through a static quenching mechanism, resulting in the formation of a ctDNA-ABT-888 complex. Thermodynamic calculations revealed that interaction was an enthalpy-driven process caused by hydrogen bonds and van der Waals forces. Competitive fluorescence experiments coupled with viscosity, CD, and FT- IR studies revealed that ABT-888 intercalates partially and binds to the groove, phosphate group, and deoxyribose sugar of ctDNA and also induces conformational changes. Molecular docking showed that ABT-888 preferably binds to the DNA groove. However, other types of binding, including classic intercalation and partial intercalation, cannot be ruled out.

• 出版日期2017
• 单位四川大学