从乙酰赖氨酸模拟配体靶向赖氨酸乙酰转移酶PCAF溴结构域解开新的同源物。,Journal of Biomolecular Structure and Dynamics

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从乙酰赖氨酸模拟配体靶向赖氨酸乙酰转移酶PCAF溴结构域解开新的同源物。
Journal of Biomolecular Structure and Dynamics ( IF 2.7 ) Pub Date : 2017-12-13 , DOI: 10.1080/07391102.2017.1415820
Venkatesan Suryanarayanan ₁ , Sanjeev Kumar Singh ₁

Affiliation

p300 / CBP相关因子（PCAF）溴结构域（BRD）（赖氨酸乙酰转移酶）已成为有希望的药物靶标，因为其功能障碍与多种疾病（如癌症，糖尿病，艾滋病等）的发作和进展有关。基于PCAF BRD的乙酰赖氨酸模拟抑制剂，生成了三种具有特征的E-药基（ARR），该抑制剂可以作为共晶结构使用（PDB ID：5FDZ）。它用于过滤小分子数据库，然后进行分子对接，因此使用富集计算进行了验证。发现产生的命中是同源物，其显示了E-Pharmacophore假说的预测能力。此外，进行了诱导拟合对接方法，结合能计算，ADME预测，单点能量计算和分子动力学模拟，以发现针对PCAF BRD的更好命中。根据结果，可以得出结论，Asn803，Tyr809和Tyr802以及水分子（HOH1001）在与抑制剂结合中起着至关重要的作用。还建议从生命化学数据库中选择四个命中点，即F2276-0099，F2276-0008，F2276-0104和F2276-0106，作为PCAF BRD的有效药物分子。因此，坚信本研究对PCAF BRD抑制剂的有效和新颖同源物的合理药物设计具有光明的影响。

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Unravelling novel congeners from acetyllysine mimicking ligand targeting a lysine acetyltransferase PCAF bromodomain.

p300/CBP Associated Factor (PCAF) bromodomain (BRD), a lysine acetyltransferases, has emerged as a promising drug target as its dysfunction is linked to onset and progression of several diseases like cancer, diabetes, AIDS, etc. In this study, a three featured E-Pharmacophore (ARR) was generated based on acetyllysine mimicking inhibitor of PCAF BRD which is available as co-crystal structure (PDB ID: 5FDZ). It was used for filtering small molecule databases followed by molecular docking and consequently validated using enrichment calculation. The resulted hits were found to be congeners which show the predictive power of E-Pharmacophore hypothesis. Further, Induced Fit Docking method, Binding energy calculation, ADME prediction, Single Point Energy calculation and Molecular Dynamics simulation were performed to find better hits against PCAF BRD. Based on the results, it was concluded that Asn803, Tyr809 and Tyr802 along with a water molecule (HOH1001) plays crucial role in binding with inhibitor. It is also proposed that four hits from Life Chemicals database namely, F2276-0099, F2276-0008, F2276-0104 and F2276-0106 could act as potent drug molecules for PCAF BRD. Thus, the present study is strongly believed to have bright impact on rational drug design of potent and novel congeners of PCAF BRD inhibitors.

更新日期：2019-11-01

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