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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Identification of high-affinity inhibitors of pyruvate dehydrogenase kinase-3: towards therapeutic management of cancer
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Identification of high-affinity inhibitors of pyruvate dehydrogenase kinase-3: towards therapeutic management of cancer

机译：丙酮酸脱氢酶激酶-3高亲和力抑制剂的鉴定：癌症治疗癌症

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Pyruvate dehydrogenase kinase 3 (PDK3) is a multifunctional enzyme that plays a central role in the cancer metabolic switch by blocking pyruvate catabolism in the TCA cycle. PDK3 plays a significant role in the TCA cycle and cancer cell progression, thus, considered as a novel drug target for developing effective therapeutics against varying types of cancer. Here, we employed a structure-based virtual high-throughput screening of natural compounds from the ZINC database to identify potential inhibitors of PDK3. First, the resulted hits were selected on the basis of their physicochemical and ADMET properties. Further, PAINS filter, binding affinities based on the docking analysis and interaction analysis was carried out to find safe and better hits against PDK3. Finally, we identified four natural compounds bearing admirable affinity towards PDK3. Selected compounds showed appreciable drug-like properties and preferentially interact to the residues of the ATP-binding pocket of PDK3. Binding and structural annotations made in docking analysis were supplemented by all-atom molecular dynamics simulations to evaluate the conformational dynamics, stability and interaction mechanism of PDK3 in complex with one of the identified compounds ZINC08764476. PDK3 and ZINC08764476 forming a stable complex throughout the simulation trajectory. We suggest that compound ZINC08764476 may be exploited as a promising scaffold for the development of potential inhibitors of PDK3 to combat cancer and associated diseases. Communicated by Ramaswamy H. Sarma
机译：丙酮酸脱氢酶激酶3（PDK3）是一种多功能酶，通过阻断TCA循环中的丙酮酸分解代谢，在癌症代谢开关中发挥中心作用。PDK3在TCA循环和癌细胞进展中起着重要作用，因此被认为是开发有效治疗各种癌症的新药物靶点。在这里，我们从锌数据库中对天然化合物进行了基于结构的虚拟高通量筛选，以确定PDK3的潜在抑制剂。首先，根据其理化性质和ADMET性质选择结果命中率。此外，还进行了基于对接分析和相互作用分析的疼痛过滤、结合亲和力分析，以找到针对PDK3的安全和更好的攻击。最后，我们鉴定了四种对PDK3具有极好亲和力的天然化合物。所选化合物显示出明显的药物样特性，并优先与PDK3的ATP结合袋残基相互作用。通过全原子分子动力学模拟，对对接分析中的结合和结构注释进行了补充，以评估PDK3与一种已鉴定化合物ZINC08764476的复合物的构象动力学、稳定性和相互作用机制。PDK3和ZINC08764476在整个模拟轨迹中形成稳定的复合体。我们认为化合物ZINC08764476可以作为一种有前途的支架，用于开发潜在的PDK3抑制剂，以对抗癌症和相关疾病。由Ramaswamy H.Sarma传达

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