Tankyrases are the group of poly (ADP-ribosyl) polymerases (PARPs) which are the attractive targets in various therapeutic areas such as cancer, antiviral, diabetes, and hormonal imbalance. The selective nature of tankyrase 1 and 2 inhibitors has created solid base to get dual site binders as they bind to induced adenosine binding site and nicotinamide binding site resulting in dual site inhibition. The present work describes the cheminformatics approach to find potential lead molecules as tankyrases dual site inhibitors through pharmacophore model by utilizing protein-ligand interaction fingerprints (PLIF) approach. The constructed pharmacophore model was used in virtually screening of ZINC and Interbioscreen database. Top ten hit molecules of virtual screening were subjected to molecular docking in order gain insights of key interactions at the adenosine and nicotinamide binding sites. The top hits were subjected to molecular dynamics simulation studies to gain deeper insights into probable mechanism of inhibition and stability of the complex. The top hit ZINC12973507 showed all the features required in key interactions at the active site of tankyrases and this hit molecule can be further explored as a potential drug candidate for dual site inhibition of tankyrases. Graphical abstract

中文翻译：

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通过蛋白质-配体相互作用指纹 (PLIF) 衍生的药效团模型、分子动力学和 ADMET 研究的虚拟筛选鉴定坦科聚合酶的双位点抑制剂

端锚聚合酶是一组聚 (ADP-核糖基) 聚合酶 (PARP)，它们是癌症、抗病毒、糖尿病和激素失衡等各种治疗领域的有吸引力的目标。端锚聚合酶 1 和 2 抑制剂的选择性为获得双位点结合物创造了坚实基础，因为它们与诱导的腺苷结合位点和烟酰胺结合位点结合，导致双位点抑制。目前的工作描述了化学信息学方法，通过利用蛋白质配体相互作用指纹 (PLIF) 方法，通过药效团模型寻找潜在的先导分子作为端锚聚合酶双位点抑制剂。构建的药效团模型用于ZINC和Interbioscreen数据库的虚拟筛选。虚拟筛选的十大热门分子进行了分子对接，以便深入了解腺苷和烟酰胺结合位点的关键相互作用。对热门产品进行分子动力学模拟研究，以更深入地了解复合物的抑制和稳定性的可能机制。最高命中的 ZINC12973507 显示了端锚聚合酶活性位点关键相互作用所需的所有特征，并且可以进一步探索该命中分子作为端锚聚合酶双位点抑制的潜在候选药物。图形概要 最高命中的 ZINC12973507 显示了端锚聚合酶活性位点关键相互作用所需的所有特征，并且可以进一步探索该命中分子作为端锚聚合酶双位点抑制的潜在候选药物。图形概要 最高命中的 ZINC12973507 显示了端锚聚合酶活性位点关键相互作用所需的所有特征，并且可以进一步探索该命中分子作为端锚聚合酶双位点抑制的潜在候选药物。图形概要