Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation.
Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation.
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DOI：
10.1208/s12248-016-9888-z
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Xie XQ
中科院分区：
文献类型：
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作者：
Feng Z;Pearce LV;Zhang Y;Xing C;Herold BK;Ma S;Hu Z;Turcios NA;Yang P;Tong Q;McCall AK;Blumberg PM;Xie XQ
瞬时受体电位香草酸1型（TRPV 1）是一种热敏性钙通道蛋白，可导致炎症以及急性和持续性疼痛。由于TRPV 1在神经元炎症信号通路中占据中心位置，因此它代表了神经炎症的高度有吸引力的潜在治疗靶点。在目前的工作中，我们已经在计算机上确定了一系列的二芳基脲类似物的hTRPV 1，其中11个化合物显示的活性在纳摩尔至微摩尔范围内，通过体外生物测定验证。然后，我们利用分子对接来探索TRPV 1和化合物之间的详细相互作用，以了解不同取代基的贡献。Tyr 511、Leu 518、Leu 547、Thr 550、Asn 551、Arg 557和Leu 670对TRPV 1识别小分子很重要。R2中的疏水基团或R1中的极性/亲水基团对TRPV 1的拮抗剂活性有显著贡献。此外，微妙的不同结合位的间氯取代对位氟的R2组转换成部分激动的拮抗作用，我们的短期分子动力学（MD）模拟预测和生物测定验证。重要的是，化合物15是我们最好的TRPV 1抑制剂之一，也显示出对大麻素受体2（CB 2）的潜在结合亲和力（1.39 μM），这是免疫炎症疾病的另一个有吸引力的靶点。此外，预测化合物1及其二芳基脲类似物靶向C-X-C趋化因子受体2（CXCR 2），尽管仍需要用这些化合物进行CXCR 2的生物测定验证。来自建模的这种预测是令人感兴趣的，因为CXCR 2也是慢性炎性疾病的潜在治疗靶点。我们的研究结果提供了开发小分子抑制剂的新策略，以同时靶向两种或更多种炎症相关蛋白，用于治疗广泛的炎症性疾病，包括具有潜在协同效应的神经炎症和神经退行性疾病。
Transient receptor potential vanilloid type 1 (TRPV1), a heat-sensitive calcium channel protein, contributes to inflammation as well as to acute and persistent pain. Since TRPV1 occupies a central position in pathways of neuronal inflammatory signaling, it represents a highly attractive potential therapeutic target for neuroinflammation. In the present work, we have in silico identified a series of diarylurea analogues for hTRPV1, of which 11 compounds showed activity in the nanomolar to micromolar range as validated by in vitro biological assays. Then, we utilized molecular docking to explore the detailed interactions between TRPV1 and the compounds to understand the contributions of the different substituent groups. Tyr511, Leu518, Leu547, Thr550, Asn551, Arg557, and Leu670 were important for the recognition of the small molecules by TRPV1. A hydrophobic group in R2 or a polar/hydrophilic group in R1 contributed significantly to the activities of the antagonists at TRPV1. In addition, the subtle different binding pose of meta-chloro in place of para-fluoro in the R2 group converted antagonism into partial agonism, as was predicted by our short-term molecular dynamics (MD) simulation and validated by bioassay. Importantly, compound 15, one of our best TRPV1 inhibitors, also showed potential binding affinity (1.39 µM) at cannabinoid receptor 2 (CB2), which is another attractive target for immune-inflammation diseases. Furthermore, compound 1 and its diarylurea analogues were predicted to target the C-X-C chemokine receptor 2 (CXCR2), although bioassay validation of CXCR2 with these compounds still needs to be performed. This prediction from the modeling is of interest, since CXCR2 is also a potential therapeutic target for chronic inflammatory diseases. Our findings provide novel strategies to develop a small molecule inhibitor to simultaneously target two or more inflammation-related proteins for the treatment of a wide range of inflammatory disorders including neuroinflammation and neurodegenerative diseases with potential synergistic effect.