Tankyrase (TNKS) belonging to the poly(ADPribose) polymerase family, are known for their multi-functioning capabilities, and play an essential role in the Wnt β-catenin pathway and various other cellular processes. Although showing inhibitory potential at a nanomolar level, the structural dual-inhibitory mechanism of the novel TNKS inhibitor, 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione, remains unexplored. By employing advanced molecular modeling, this study provides these insights. Results of sequence alignments of binding site residues identified conserved residues; GLY1185 and ILE1224 in TNKS-1 and PHE1035 and PRO1034 in TNKS-2 as crucial mediators of the dual binding mechanism of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione, corroborated by high per-residue energy contributions and consistent high-affinity interactions of these residues. Estimation of the binding free energy of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione showed estimated total energy of −43.88 kcal/mol and −30.79 kcal/mol towards TNKS-1 and 2, respectively, indicating favorable analogous dual binding as previously reported. Assessment of the conformational dynamics of TNKS-1 and 2 upon the binding of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione revealed similar structural changes characterized by increased flexibility and solvent assessible surface area of the residues inferring an analogous structural binding mechanism. Insights from this study show that peculiar, conserved residues are the driving force behind the dual inhibitory mechanism of 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione and could aid in the design of novel dual inhibitors of TNKS-1 and 2 with improved therapeutic properties.

Tankyrase (TNKS) 属于聚 (ADPribose) 聚合酶家族，以其多功能能力而闻名，并且在 Wnt β-连环蛋白途径和各种其他细胞过程中发挥重要作用。尽管在纳摩尔水平上显示出抑制潜力，但新型 TNKS 抑制剂 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4 的结构双重抑制机制-二酮，仍未开发。通过采用先进的分子模型，本研究提供了这些见解。结合位点残基的序列比对结果鉴定出保守残基；TNKS-1 中的 GLY1185 和 ILE1224 以及 TNKS-2 中的 PHE1035 和 PRO1034 作为 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-双重结合机制的关键介质2,4-二酮，由高的每个残基能量贡献和这些残基的一致的高亲和力相互作用证实。5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione 的结合自由能的估计显示估计的总能量为 -43.88 kcal/mol 和 -对 TNKS-1 和 2 分别为 30.79 kcal/mol，表明如先前报道的有利的类似双重结合。TNKS-1 和 2 在 5-methyl-5-[4-(4-oxo-3H-quinazolin-2-yl)phenyl]imidazolidine-2,4-dione 结合后的构象动力学评估揭示了类似的结构变化其特征在于增加的灵活性和溶剂可评估的残基表面积，从而推断出类似的结构结合机制。这项研究的见解表明，