Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
West African Centre for Computational Analysis, Accra, Ghana.
Cell Biochem Biophys. 2022 Sep;80(3):505-518. doi: 10.1007/s12013-022-01076-2. Epub 2022 May 30.
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）属于多聚（ADP-核糖）聚合酶家族，以其多功能特性而闻名，在 Wnt β-连环蛋白途径和各种其他细胞过程中发挥着重要作用。虽然新型 TNKS 抑制剂 5-甲基-5-[4-(4-氧代-3H-喹唑啉-2-基)苯基]咪唑烷-2,4-二酮在纳摩尔水平表现出抑制潜力，但该抑制剂的结构双重抑制机制仍未得到探索。本研究通过先进的分子建模提供了这些见解。结合位点残基序列比对结果确定了保守残基；TNKS-1 中的 GLU1185 和 ILE1224 以及 TNKS-2 中的 PHE1035 和 PRO1034 是 5-甲基-5-[4-(4-氧代-3H-喹唑啉-2-基)苯基]咪唑烷-2,4-二酮双重结合机制的关键介质，这得到了高残基能量贡献和这些残基一致的高亲和力相互作用的支持。5-甲基-5-[4-(4-氧代-3H-喹唑啉-2-基)苯基]咪唑烷-2,4-二酮结合自由能的估算表明，其对 TNKS-1 和 2 的总结合能分别为-43.88 kcal/mol 和-30.79 kcal/mol，表明与之前报道的类似的双重结合有利。评估 TNKS-1 和 2 与 5-甲基-5-[4-(4-氧代-3H-喹唑啉-2-基)苯基]咪唑烷-2,4-二酮结合时的构象动力学表明，类似的结构变化特征是残基的柔韧性增加和溶剂可及表面积增加，推断出类似的结构结合机制。本研究的结果表明，独特的保守残基是 5-甲基-5-[4-(4-氧代-3H-喹唑啉-2-基)苯基]咪唑烷-2,4-二酮双重抑制机制的驱动力，并有助于设计具有改善治疗特性的新型 TNKS-1 和 2 的双重抑制剂。
