Structural modification of indomethacin toward selective inhibition of COX-2 with a significant increase in van der Waals contributions |
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| Authors: | Akari Ikeda Eishi Funakoshi Mitsugu Araki Biao Ma Yukiko Karuo Atsushi Tarui Kazuyuki Sato Yasushi Okuno Kentaro Kawai Masaaki Omote |
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| Affiliation: | 1. Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan;2. Faculty of Science and Engineering, Setsunan University, 17-8 Ikedanaka-machi, Neyagawa, Osaka 573-8508, Japan;3. Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan;4. Research and Development Group for In Silico Drug Discovery, Center for Cluster Development and Coordination (CCD), Foundation for Biomedical Research and Innovation at Kobe (FBRI), 6-3-5, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan;5. Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan |
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| Abstract: | We have synthesized a fluorinated analogue of indomethacin bearing a 3,3,3-trifluoroprop-1-enyl group at its 2-position and evaluated its inhibitory activity towards the COX-1 and COX-2 enzymes in vitro. The results revealed that this fluorinated analogue exhibited much greater inhibitory activity and selectivity towards COX-2 than indomethacin. The increased affinity between the fluorinated analogue and COX-2 was attributed to a significant increase in van der Waals contacts (i.e. van der Waals contributions in ΔG were ?13.80?kcal/mol for COX-1 and ?18.46?kcal/mol for COX-2), explaining an effect of the fluorine substituent in enzyme selectivity. This newly synthesized fluorinated analogue therefore represents a potent and selective COX-2 inhibitor. |
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| Keywords: | Indomethacin 3,3,3-Trifluoroprop-1-enyl group COX-2 selective inhibition van der Waals contribution |
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