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首页> 外文期刊>Structural Chemistry >Identification of dual site inhibitors of tankyrase through virtual screening of protein-ligand interaction fingerprint (PLIF)-derived pharmacophore models, molecular dynamics, and ADMET studies
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Identification of dual site inhibitors of tankyrase through virtual screening of protein-ligand interaction fingerprint (PLIF)-derived pharmacophore models, molecular dynamics, and ADMET studies

机译：通过虚拟筛选蛋白质 - 配体相互作用指纹（PLIF）的药物团模型，分子动力学和呼叫研究

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摘要

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.
机译：甲状腺酶是聚（ADP-核糖基）聚合酶（PARP）的基团，其是各种治疗区域的有吸引力的靶标，例如癌症，抗病毒，糖尿病和激素不平衡。 Tankyrase 1和2抑制剂的选择性性质已经产生固体碱，以获得双位点粘合剂，因为它们结合诱导的腺苷结合位点和烟酰胺结合位点，导致双位点抑制。本作本作者描述了通过使用蛋白质 - 配体相互作用指纹（PLIF）方法，通过药物团模型来找到潜在的铅分子作为罐子双位点抑制剂的化学信息学方法。构建的药效线模型实际上用于锌和杂交屏幕数据库。在腺苷和烟胺酰胺结合位点的关键相互作用的识别下，对虚拟筛选的前十个命中分子进行分子对接。顶部命中令人欣赏到分子动力学模拟研究，以获得更深入的抑制机制和复合物的稳定性机制。顶部HIT ZINC12973507展示了乳蛋白活性位点的关键相互作用所需的所有特征，并且这种打击分子可以进一步探索作为对吡酶的双位点抑制的潜在药物候选物。

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