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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Elucidation of different inhibition mechanism of small chemicals on PtdInsP-binding domains using in silico docking experiments
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Elucidation of different inhibition mechanism of small chemicals on PtdInsP-binding domains using in silico docking experiments

机译：利用计算机对接实验阐明了小化学物质对PtdInsP结合域的不同抑制机制

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摘要

Phosphatidylinositides, most negatively charged lipids in cellular membranes, regulate diverse effector proteins through the interaction with their lipid binding domains. We have previously reported inhibitory effect of small chemicals on the interaction between PtdIns(3,4,5)P3 and Btk PH domain. Here, we report that the inhibitory effects of same sets of chemicals on Grp1 PH domain and epsin1 ENTH domain to elucidate diversity of inhibitory mechanisms upon different lipid binding domains. Among the chemicals, chemical 8 showed best inhibition in vitro assay for Grp1 PH domain and epsin1 ENTH domain, and then the interaction between small chemicals and lipid binding domains was further investigated by in silico docking experiments. As a result, it was concluded that the diverse inhibitory effects on different lipid binding domains were dependent on not only the number of interactions between small chemical and domain, but also additional interaction with positively charged surfaces as the secondary binding sites. This finding will help to develop lipid binding inhibitors as antagonists for lipid-protein interactions, and these inhibitors would be novel therapeutic drug candidates via regulating effector proteins involved in severe human diseases.
机译：磷脂酰肌醇，是细胞膜中带负电荷最多的脂质，通过与其脂质结合域的相互作用来调节多种效应蛋白。我们以前曾报道过小化学物质对PtdIns（3,4,5）P3和Btk PH域之间相互作用的抑制作用。在这里，我们报告说，相同的化学品对Grp1 PH域和epsin1 ENTH域的抑制作用，以阐明对不同脂质结合域的抑制机制的多样性。在化学药品中，化学药品8对Grp1 PH结构域和epsin1 ENTH结构域表现出最佳的抑制作用，然后通过计算机对接实验进一步研究了小型化学药品与脂质结合结构域之间的相互作用。结果，得出的结论是，对不同脂质结合结构域的多种抑制作用不仅取决于小化学物质与结构域之间相互作用的数量，还取决于与带正电荷的表面作为次级结合位点的其他相互作用。该发现将有助于开发脂质结合抑制剂作为脂质-蛋白质相互作用的拮抗剂，并且这些抑制剂将通过调节与严重人类疾病有关的效应蛋白而成为新颖的治疗药物候选物。

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