Comparative modeling and virtual screening for the identification of novel inhibitors for myo-inositol-1-phosphate synthase
Comparative modeling and virtual screening for the identification of novel inhibitors for myo-inositol-1-phosphate synthase
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DOI：
10.1007/s11033-014-3370-8
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发表时间：
2014-08-01
影响因子：
2.8
通讯作者：
Abro, Asma
中科院分区：
文献类型：
--
作者：
Azam, Syed Sikander;Sarfaraz, Sara;Abro, Asma
肌醇-1-磷酸(MIP)合成酶是肌醇生物合成途径中的关键酶。肌醇信号通路的中断与双相情感障碍有关。以往的工作表明，MIP合成酶可能是抗双相情感药物开发的一个有吸引力的靶点。抑制这种酶可能有助于降低患者患病的风险。以此为目标，建立了蛋白质的三维结构模型，并对其活性中心进行了预测。第一次，进行了计算研究，以获得对这种酶与配体相互作用行为的结构见解。使用OpenEye科学软件的Filter、ROCS和EON模块进行虚拟筛选。锌数据库中的天然产物被用于筛选过程。使用FRED(快速刚性穷举对接)和GOLD(配基对接遗传优化)对接程序将得到的化合物对接到目标蛋白质的活性部位。分析表明，广泛的氢键网络和疏水相互作用在配体结合中起着重要的作用。四种化合物入围，它们的结合分析正在进行中。
Myo-inositol-1-phosphate (MIP) synthase is a key enzyme in the myo-inositol biosynthesis pathway. Disruption of the inositol signaling pathway is associated with bipolar disorders. Previous work suggested that MIP synthase could be an attractive target for the development of anti-bipolar drugs. Inhibition of this enzyme could possibly help in reducing the risk of a disease in patients. With this objective, three dimensional structure of the protein was modeled followed by the active site prediction. For the first time, computational studies were carried out to obtain structural insights into the interactive behavior of this enzyme with ligands. Virtual screening was carried out using FILTER, ROCS and EON modules of the OpenEye scientific software. Natural products from the ZINC database were used for the screening process. Resulting compounds were docked into active site of the target protein using FRED (Fast Rigid Exhaustive Docking) and GOLD (Genetic Optimization for Ligand Docking) docking programs. The analysis indicated extensive hydrogen bonding network and hydrophobic interactions which play a significant role in ligand binding. Four compounds are shortlisted and their binding assay analysis is underway.