Peters Xylia Q, Poonan Preantha, Salifu Elliasu Y, Alahmdi Mohamed I, Abo-Dya Nader E, Soliman Mahmoud E S
Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk, 7149, Saudi Arabia.
Curr Pharm Biotechnol. 2025;26(2):222-234. doi: 10.2174/1389201024666230330084017.
Tankyrases (TNKS) are homomultimers existing in two forms, viz. TNKS1 and TNKS2. TNKS2 plays a pivotal role in carcinogenesis by activating the Wnt//β- catenin pathway. TNKS2 has been identified as a suitable target in oncology due to its crucial role in mediating tumour progression. The discovery of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl) phenyl]imidazolidine-2,4-dione, a hydantoin phenylquinazolinone derivative which exists as a racemic mixture and in its pure enantiomer forms, has reportedly exhibited inhibitory potency towards TNKS2. However, the molecular events surrounding its chirality towards TNKS2 remain unresolved.
Herein, we employed methods such as molecular dynamics simulation coupled with binding free energy estimations to explore the mechanistic activity of the racemic inhibitor and its enantiomer forms on TNKS2 at a molecular level.
Favourable binding free energies were noted for all three ligands propelled by electrostatic and van der Waals forces. The positive enantiomer demonstrated the highest total binding free energy (-38.15 kcal/mol), exhibiting a more potent binding affinity to TNKS2. Amino acids PHE1035, ALA1038, and HIS1048; PHE1035, HIS1048 and ILE1039; and TYR1060, SER1033 and ILE1059 were identified as key drivers of TNKS2 inhibition for all three inhibitors, characterized by the contribution of highest residual energies and the formation of crucial high-affinity interactions with the bound inhibitors. Further assessment of chirality by the inhibitors revealed a stabilizing effect of the complex systems of all three inhibitors on the TNKS2 structure. Concerning flexibility and mobility, the racemic inhibitor and negative enantiomer revealed a more rigid structure when bound to TNKS2, which could potentiate biological activity interference. The positive enantiomer, however, displayed much more elasticity and flexibility when bound to TNKS2.
Overall, 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione and its derivatives showed their inhibitory prowess when bound to the TNKS2 target via in silico assessment. Thus, results from this study offer insight into chirality and the possibility of adjustments of the enantiomer ratio to promote greater inhibitory results. These results could also offer insight into lead optimization to enhance inhibitory effects.
端锚聚合酶（TNKS）是以两种形式存在的同多聚体，即TNKS1和TNKS2。TNKS2通过激活Wnt/β-连环蛋白途径在致癌过程中起关键作用。由于TNKS2在介导肿瘤进展中起关键作用，已被确定为肿瘤学中的一个合适靶点。据报道，5-甲基-5-[4-(4-氧代-3H-喹唑啉-2-基)苯基]咪唑烷-2,4-二酮（一种以消旋混合物及其纯对映体形式存在的乙内酰脲苯基喹唑啉酮衍生物）对TNKS2具有抑制活性。然而，围绕其对TNKS2手性的分子事件仍未得到解决。
在此，我们采用分子动力学模拟结合结合自由能估计等方法，在分子水平上探索消旋抑制剂及其对映体形式对TNKS2的作用机制。
在静电和范德华力的推动下，所有三种配体都具有良好的结合自由能。正对映体表现出最高的总结合自由能（-38.15 kcal/mol），对TNKS2表现出更强的结合亲和力。氨基酸PHE1035、ALA1038和HIS1048；PHE1035、HIS1048和ILE1039；以及TYR1060、SER1033和ILE1059被确定为所有三种抑制剂抑制TNKS2的关键驱动因素，其特征是具有最高的剩余能量贡献以及与结合的抑制剂形成关键的高亲和力相互作用。抑制剂对手性的进一步评估揭示了所有三种抑制剂的复合系统对TNKS2结构的稳定作用。关于柔韧性和流动性，消旋抑制剂和负对映体在与TNKS2结合时显示出更刚性的结构，这可能会增强生物活性干扰。然而，正对映体在与TNKS2结合时表现出更大的弹性和柔韧性。
总体而言，5-甲基-5-[4-(4-氧代-3H-喹唑啉-2-基)苯基]咪唑烷-2,4-二酮及其衍生物通过计算机模拟评估显示出与TNKS2靶点结合时的抑制能力。因此，本研究结果为手性以及调整对映体比例以促进更大抑制效果的可能性提供了见解。这些结果也可为先导化合物优化以增强抑制作用提供见解。
