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Fusion of Structure and Ligand Based Methods for Identification of Novel CDK2 Inhibitors
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2017-08-03 00:00:00 , DOI: 10.1021/acs.jcim.7b00293
Priya Mahajan 1 , Gousia Chashoo 1 , Monika Gupta 1 , Amit Kumar 1 , Parvinder Pal Singh 1 , Amit Nargotra 1
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2017-08-03 00:00:00 , DOI: 10.1021/acs.jcim.7b00293
Priya Mahajan 1 , Gousia Chashoo 1 , Monika Gupta 1 , Amit Kumar 1 , Parvinder Pal Singh 1 , Amit Nargotra 1
Affiliation
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Cyclin dependent kinases play a central role in cell cycle regulation which makes them a promising target with multifarious therapeutic potential. CDK2 regulates various events of the eukaryotic cell division cycle, and the pharmacological evidence indicates that overexpression of CDK2 causes abnormal cell-cycle regulation, which is directly associated with hyperproliferation of cancer cells. Therefore, CDK2 is regarded as a potential target molecule for anticancer medication. Thus, to decline CDK2 activity by potential lead compounds has proved to be an effective treatment for cancer. The availability of a large number of X-ray crystal structures and known inhibitors of CDK2 provides a gateway to perform efficient computational studies on this target. With the aim to identify new chemical entities from commercial libraries, with increased inhibitory potency for CDK2, ligand and structure based computational drug designing approaches were applied. A druglike library of 50,000 compounds from ChemDiv and ChemBridge databases was screened against CDK2, and 110 compounds were identified using the parallel application of these models. On in vitro evaluation of 40 compounds, seven compounds were found to have more than 50% inhibition at 10 μM. MD studies of the hits revealed the stability of these inhibitors and pivotal role of Glu81 and Leu83 for binding with CDK2. The overall study resulted in the identification of four new chemical entities possessing CDK2 inhibitory activity.
中文翻译：
基于结构和配体的融合方法用于鉴定新型CDK2抑制剂
细胞周期蛋白依赖性激酶在细胞周期调控中起着核心作用，这使其成为具有广泛治疗潜力的有希望的靶标。CDK2调节真核细胞分裂周期的各种事件，并且药理学证据表明CDK2的过表达引起异常的细胞周期调节，这直接与癌细胞的过度增殖有关。因此，CDK2被认为是抗癌药物的潜在靶分子。因此，已证明通过潜在的先导化合物降低CDK2活性是治疗癌症的有效方法。大量的X射线晶体结构和已知的CDK2抑制剂的可用性为在该目标上进行有效的计算研究提供了途径。为了从商业图书馆中识别新的化学实体，随着对CDK2抑制力的提高，应用了基于配体和结构的计算药物设计方法。使用ChemDiv和ChemBridge数据库中的50,000种化合物的类药物库，针对CDK2进行了筛选，并使用这些模型的并行应用鉴定出110种化合物。上在对40种化合物的体外评估中，发现7种化合物在10μM时具有超过50％的抑制作用。命中的MD研究揭示了这些抑制剂的稳定性以及Glu81和Leu83与CDK2结合的关键作用。总体研究确定了具有CDK2抑制活性的四个新化学实体。
更新日期：2017-08-03
中文翻译：
基于结构和配体的融合方法用于鉴定新型CDK2抑制剂
细胞周期蛋白依赖性激酶在细胞周期调控中起着核心作用，这使其成为具有广泛治疗潜力的有希望的靶标。CDK2调节真核细胞分裂周期的各种事件，并且药理学证据表明CDK2的过表达引起异常的细胞周期调节，这直接与癌细胞的过度增殖有关。因此，CDK2被认为是抗癌药物的潜在靶分子。因此，已证明通过潜在的先导化合物降低CDK2活性是治疗癌症的有效方法。大量的X射线晶体结构和已知的CDK2抑制剂的可用性为在该目标上进行有效的计算研究提供了途径。为了从商业图书馆中识别新的化学实体，随着对CDK2抑制力的提高，应用了基于配体和结构的计算药物设计方法。使用ChemDiv和ChemBridge数据库中的50,000种化合物的类药物库，针对CDK2进行了筛选，并使用这些模型的并行应用鉴定出110种化合物。上在对40种化合物的体外评估中，发现7种化合物在10μM时具有超过50％的抑制作用。命中的MD研究揭示了这些抑制剂的稳定性以及Glu81和Leu83与CDK2结合的关键作用。总体研究确定了具有CDK2抑制活性的四个新化学实体。
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