Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
Cell Biochem Biophys. 2022 Sep;80(3):495-504. doi: 10.1007/s12013-022-01075-3. Epub 2022 May 19.
In recent times, inhibition of poly (ADP-ribose) polymerase (PARP) enzymes by pharmacological drugs has attracted much attention as an anticancer therapy. As reported, PARP-16 has been discovered as a novel anticancer target for small cell lung cancer, and that the inhibition of both PARP-16 and PARP-1 by talazoparib can increase the overall effectiveness of talazoparib in the SCLC treatment. In this study, we employed computational approaches to investigate the differential inhibitory potency of Talazoparib on PARP-1 and PARP-16. Talazoparib has excellent PARP-1 and PARP-16 binding activities, as revealed by the ΔG (total binding energy). Pp16-tpb had binding energy of -34.85 kcal/mol, while pp1-tpb had a binding energy of -26.36 kcal/mol. The binding activity of Talazoparib on both PARP-1 and PARP-16 was significantly influenced by van der Waal and electrostatic interactions. Correspondingly, according to the findings of this study, binding residues with total binding energy greater than 1.00 kcal/mol contributed considerably to the Talazoparib's binding activities on PARP-1 and PARP-16. We believe the findings of this study will pave the way for developing dual targeting of PARP enzymes as a strategy for small-cell lung cancer treatment.
近年来，通过药理学药物抑制聚（ADP-核糖）聚合酶（PARP）已成为一种备受关注的抗癌疗法。据报道，PARP-16 已被发现为小细胞肺癌的一种新的抗癌靶点，而他拉唑帕尼对 PARP-16 和 PARP-1 的抑制作用可以提高他拉唑帕尼在 SCLC 治疗中的整体疗效。在这项研究中，我们采用计算方法研究了他拉唑帕尼对 PARP-1 和 PARP-16 的抑制作用。Talazoparib 对 PARP-1 和 PARP-16 具有出色的结合活性，这一点通过 ΔG（总结合能）得到了证实。Pp16-tpb 的结合能为-34.85 kcal/mol，而 pp1-tpb 的结合能为-26.36 kcal/mol。Talazoparib 对 PARP-1 和 PARP-16 的结合活性受到范德华力和静电相互作用的显著影响。相应地，根据本研究的结果，总结合能大于 1.00 kcal/mol 的结合残基对 Talazoparib 在 PARP-1 和 PARP-16 上的结合活性有很大贡献。我们相信本研究的结果将为开发 PARP 酶的双重靶向作为小细胞肺癌治疗策略铺平道路。
