Magesh Sadagopan, Savita Vats, Moriya Setsuko, Suzuki Tohru, Miyagi Taeko, Ishida Hideharu, Kiso Makoto
Department of Applied Bioorganic Chemistry, Faculty of Applied Biological Sciences, Gifu University, Japan.
Bioorg Med Chem. 2009 Jul 1;17(13):4595-603. doi: 10.1016/j.bmc.2009.04.065. Epub 2009 May 4.
Recent advances in the sialidase biology have clarified the role of human sialidases (NEU 1 to NEU4) in the development of various disease states such as cancer, diabetes and arteriosclerosis. Isoform selective human sialidase inhibitors could be a therapeutic tool or molecular probes for the exploration of the specific functions of human sialidases. In the present study, de novo design based virtual screening was performed to find a new class of human sialidase inhibitors using the experimental crystal structure of NEU2 isoform. A few of nitro benzene and fluoro benzoic acid were identified and a series of 4-acetamido-5-acylamido-2-fluoro benzoic acids were synthesized and, the inhibitory activity of all these compounds against all human sialidase enzymes was evaluated. All these compounds were found to have a poor inhibitory activity and only NEU2 showed more sensitivity to this series of compounds as compared to other isoforms. Molecular docking was performed to gain insight regarding the binding mode of these inhibitors and thereby provided valuable information for our study on the design of selective human sialidase inhibitors further.
唾液酸酶生物学的最新进展阐明了人类唾液酸酶（NEU 1至NEU4）在诸如癌症、糖尿病和动脉硬化等各种疾病状态发展中的作用。亚型选择性人类唾液酸酶抑制剂可能是用于探索人类唾液酸酶特定功能的治疗工具或分子探针。在本研究中，利用NEU2亚型的实验晶体结构进行了基于从头设计的虚拟筛选，以寻找一类新型的人类唾液酸酶抑制剂。鉴定出了一些硝基苯和氟苯甲酸，并合成了一系列4-乙酰氨基-5-酰氨基-2-氟苯甲酸，评估了所有这些化合物对所有人类唾液酸酶的抑制活性。发现所有这些化合物的抑制活性都很差，与其他亚型相比，只有NEU2对这一系列化合物表现出更高的敏感性。进行了分子对接以深入了解这些抑制剂的结合模式，从而为我们进一步研究选择性人类唾液酸酶抑制剂的设计提供了有价值的信息。
