期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 13, 页码 4619-4626出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm200310q
关键词
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资金
- The Netherlands Organization for Scientific Research (NWO)
- Dutch Cancer Society (KWF)
- The Netherlands Proteomics Centre
Autotaxin (ATX) is a secreted phosphodiesterase that hydrolyzes the abundant phospholipid lysophosphatidylcholine (LPC) to produce lysophosphatidic acid (LPA). The ATX-LPA signaling axis has been implicated in inflammation, fibrosis, and tumor progression, rendering ATX an attractive drug target. We recently described a boronic add-based inhibitor of ATX, named HA155 (1). Here, we report the design of new inhibitors based on the crystal structure of ATX in complex with inhibitor 1. Furthermore, we describe the syntheses and activities of these new inhibitors, whose potencies can be explained by structural data. To understand the difference in activity between two different isomers with nanomolar potencies, we performed molecular docking experiments. Intriguingly, molecular docking suggested a remarkable binding pose for one of the isomers, which differs from the original binding pose of inhibitor 1 for ATX, opening further options for inhibitor design.
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