Department of Radiotherapy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.
Department of Biochemistry and Molecular Biology, Hainan Medical University, Haikou 571199, China.
Molecules. 2023 Feb 15;28(4):1829. doi: 10.3390/molecules28041829.
The protein PARP1, which plays a crucial role in DNA repair processes, is an attractive target for cancer therapy, especially for BRCA-deficient cancers. To overcome the acquired drug resistance of PARP1, G-quadruplex (G4) identified in the PARP1-promotor region is gaining increasing attention. Aiming to explore the molecular mechanism of PARP1 inhibition with G4 and PARP1 as potential targets, a comparative investigation of the binding characteristics of the newly identified G4 stabilizer MTR-106, which showed modest activity against talazoparib-resistant xenograft models and the FDA-approved PARP1 inhibitor (PARPi) talazoparib, were performed through molecular simulations. Combined analyses revealed that, relative to the groove binding of talazoparib, MTR-106 induced the formation of a sandwich framework through stacking with dT and the capping G-pair (dG and dG) of G4 to present largely enhanced binding affinity. For the binding with PARP1, although both were located in the catalytic pocket of PARP1, MTR-106 formed more extensive interactions with the surrounding PARP1 residues compared to talazoparib, in line with its increased binding strength. Importantly, vdW interaction was recognized as a decisive factor in the bindings with G4 and PARP1. Collectively, these findings demonstrated the ascendancy of MTR-106 over talazoparib at the atomic level and revealed that the dual targeting of G4 and PARP1 might be pivotal for PARPi that is capable of overcoming acquired drug resistance, providing valuable information for the design and development of novel drugs.
PARP1 蛋白在 DNA 修复过程中起着至关重要的作用，是癌症治疗的一个有吸引力的靶点，特别是对于 BRCA 缺陷型癌症。为了克服 PARP1 的获得性耐药性，PARP1 启动子区域中鉴定的 G-四链体（G4）越来越受到关注。为了探索 G4 和 PARP1 作为潜在靶点抑制 PARP1 的分子机制，对新鉴定的 G4 稳定剂 MTR-106 的结合特性进行了比较研究，MTR-106 对塔拉唑帕利耐药异种移植模型表现出适度的活性，且为 FDA 批准的 PARP1 抑制剂（PARPi）。通过分子模拟，对 MTR-106 与新鉴定的 G4 稳定剂 MTR-106 的结合特性进行了比较研究，MTR-106 对塔拉唑帕利耐药异种移植模型表现出适度的活性，且为 FDA 批准的 PARP1 抑制剂（PARPi）。通过分子模拟，对 MTR-106 与新鉴定的 G4 稳定剂 MTR-106 的结合特性进行了比较研究，MTR-106 对塔拉唑帕利耐药异种移植模型表现出适度的活性，且为 FDA 批准的 PARP1 抑制剂（PARPi）。结合分析表明，与塔拉唑帕利的沟结合相比，MTR-106 通过与 dT 和 G4 的盖帽 G 对（dG 和 dG）堆叠诱导三明治框架的形成，表现出大大增强的结合亲和力。对于与 PARP1 的结合，尽管两者都位于 PARP1 的催化口袋中，但 MTR-106 与周围 PARP1 残基形成的相互作用比塔拉唑帕利更广泛，这与它的结合强度增加一致。重要的是，vdW 相互作用被认为是与 G4 和 PARP1 结合的决定性因素。总的来说，这些发现从原子水平上证明了 MTR-106 优于塔拉唑帕利，揭示了 G4 和 PARP1 的双重靶向可能对克服获得性耐药性的 PARPi 至关重要，为新型药物的设计和开发提供了有价值的信息。
