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首页> 外文期刊>RSC Advances >Novel poly(ADP-ribose) polymerase inhibitor veliparib: biophysical studies on its binding to calf thymus DNA
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Novel poly(ADP-ribose) polymerase inhibitor veliparib: biophysical studies on its binding to calf thymus DNA

机译：新型聚（ADP-核糖）聚合酶抑制剂维利帕利布：与小牛胸腺DNA结合的生物物理研究

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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.
机译：Veliparib（ABT-888）可以通过阻断DNA碱基切除修复来抑制癌症的生长，是最近开发的几种聚（ADP-核糖）聚合酶口服抑制剂之一，目前已在临床试验中使用。在这项工作中，首先通过紫外线可见吸收，核磁共振（NMR）光谱，稳态和时间分辨荧光，粘度测量，圆二色性（CD）研究小牛胸腺DNA（ctDNA）与ABT-888的相互作用。 ，傅立叶红外光谱（FT-IR）以及分子对接方法。紫外可见吸收表明ABT-888确实与ctDNA结合。质子NMR谱中ABT-888的质子峰的展宽和高场移位表明，ABT-888主要通过部分插入与ctDNA相互作用。荧光猝灭和时间分辨荧光光谱研究表明，ABT-888与ctDNA的结合是通过静态猝灭机制发生的，从而导致了ctDNA-ABT-888复合物的形成。热力学计算表明，相互作用是由氢键和范德华力引起的焓驱动过程。竞争性荧光实验加上粘度，CD和FT-IR研究表明，ABT-888部分插入并与ctDNA的凹槽，磷酸基团和脱氧核糖结合，并诱导构象变化。分子对接表明，ABT-888优选与DNA凹槽结合。但是，不能排除其他类型的绑定，包括经典插值和部分插值。

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