In recent years, tankyrase inhibition has gained a great focus as an anti-cancer strategy due to their modulatory effect on WNT/β-catenin pathway implicated in many malignancies, including colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). Based on the structural homology in the catalytic domain of PARP enzymes, bis-quinazolinone 5 (Cpd 5) was designed to be a potent selective tankyrase inhibitor. In this study, we employed molecular dynamics simulations and binding energy analysis to decipher the underlying mechanism of TNK-1 inhibition by Cpd 5 in comparison with a known selective tankyrase, IWR-1. The Cpd 5 had a relatively higher ΔG_bind than IWR-1 from the thermodynamics analysis, revealing the better inhibitory activity of Cpd 5 compared to IWR-1. High involvement of solvation energy (ΔG_sol) and the van der Waals energy (ΔE_vdW) potentiated the affinity of Cpd 5 at TNK-1 active site. Interestingly, the keto group and the N3 atom of the quinazolinone nucleus of Cpd 5, occupying the NAM subsite, was able to form H-bond with Gly1185, thereby favoring the better stability and higher inhibitory efficacy of Cpd 5 relative to IWR-1. Our analysis proved that the firm binding of Cpd 5 was achieved by the quinazolinone groups via the hydrophobic interactions with the side chains of key site residues at the two subsite regions: His1201, Phe1188, Ala1191, and Ile1192 at the AD subsite and Tyr1224, Tyr1213, and Ala1215 at the NAM subsite. Thus, Cpd 5 is dominantly bound through π-π stacked interactions and other hydrophobic interactions. We believe that findings from this study would provide an important rationale towards the structure-based design of improved selective tankyrase inhibitors in cancer therapy.

近年来，tankyrase 抑制作为一种抗癌策略受到了广泛关注，因为它们对 WNT/β-catenin 通路的调节作用与许多恶性肿瘤有关，包括结肠直肠癌 (CRC) 和非小细胞肺癌 (NSCLC) . 基于 PARP 酶催化域的结构同源性，双喹唑啉酮 5 (Cpd 5) 被设计为一种有效的选择性坦聚合酶抑制剂。在这项研究中，我们采用分子动力学模拟和结合能分析来破译 Cpd 5 与已知的选择性坦聚合酶 IWR-1 相比抑制 TNK-1 的潜在机制。Cpd 5 具有相对较高的 Δ G_结合热力学分析显示 Cpd 5 的抑制活性优于 IWR-1。溶剂化能 (Δ G _sol ) 和范德华能 (Δ E _vdW ) 的高度参与) 增强了 Cpd 5 在 TNK-1 活性位点的亲和力。有趣的是，占据NAM亚位的Cpd 5的喹唑啉酮核的酮基和N3原子能够与Gly1185形成H键，从而有利于Cpd 5相对于IWR-1具有更好的稳定性和更高的抑制功效。我们的分析证明，喹唑啉酮基团通过与两个亚位点区域的关键位点残基侧链的疏水相互作用实现了 Cpd 5 的牢固结合：在 AD 亚位点的 His1201、Phe1188、Ala1191 和 Ile1192 以及 Tyr1224、Tyr1213 ，和 Ala1215 在 NAM 子站点。因此，Cpd 5 主要通过 π-π 堆叠相互作用和其他疏水相互作用结合。