Discovery of Biphenyl-Sulfonamides as Novel β-N-Acetyl-D-Hexosaminidase Inhibitors via Structure-Based Virtual Screening
Discovery of Biphenyl-Sulfonamides as Novel β-N-Acetyl-D-Hexosaminidase Inhibitors via Structure-Based Virtual Screening
复制标题
通过基于结构的虚拟筛选发现联苯磺酰胺作为新型 β-N-乙酰基-D-己糖胺酶抑制剂
DOI：
10.1021/acs.jafc.1c01642
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发表时间：
2021-09-30
影响因子：
6.1
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
--
作者：
Chen, Tao;Li, Wen-Qin;Yang, Guang-Fu
由于抗药性的发展，人们总是需要新的杀虫靶点。 OfHex1 是在亚洲玉米螟 (Ostrinia fnacalis) 中发现的一种 β-N-乙酰基-D-己糖胺酶，参与昆虫几丁质分解代谢，并已被证明是杀虫剂开发的理想靶标。本研究通过基于结构的虚拟筛选、结构简化和生物学评价，表明具有联苯磺酰胺骨架的化合物作为OfHex1抑制剂具有巨大的潜力。具体而言，化合物 10k、10u 和 10v 的 K-i 值分别为 4.30、3.72 和 4.56 μM，因此，它们比一些报道的非糖基抑制剂更有效，例如 phlegmacin B-1 (K-i = 26 μM)、小檗碱 = 12 μM)、2 (K-i = 11.2 μM) 和3（K-i=28.9μM）。此外，抑制动力学评估表明，目标化合物是相对于底物的竞争性抑制剂，并且根据毒性预测，它们中的大多数具有有效的药物特性。所得结果表明，联苯磺酰胺骨架具有化学结构简单、合成容易、活性强、毒性低等特点，在以OfHex1为靶标的害虫防治方面具有进一步开发的潜力。
Novel insecticidal targets are always in demand due to the development of resistance. OfHex1, a beta-N-acetyl-D-hexosaminidase identified in Ostrinia furnacalis (Asian corn borer), is involved in insect chitin catabolism and has proven an ideal target for insecticide development. In this study, structure-based virtual screening, structure simplification, and biological evaluation are used to show that compounds with a biphenyl-sulfonamide skeleton have great potential as OfHex1 inhibitors. Specifically, compounds 10k, 10u, and 10v have K-i values of 4.30, 3.72, and 4.56 mu M, respectively, and thus, they are more potent than some reported nonglycosyl-based inhibitors such as phlegmacin B-1 (K-i = 26 mu M), berberine = 12 mu M), 2 (K-i = 11.2 mu M), and 3 (K-i = 28.9 mu M). Furthermore, inhibitory kinetic assessments reveal that the target compounds are competitive inhibitors with respect substrate, and based on toxicity predictions, most of them have potent drug properties. The obtained results indicate that the biphenyl-sulfonamide skeleton characterized by simple chemical structure, synthetic tractability, potent activity, and low toxicity has potential for further development in pest management targeting OfHex1.